Ependymoma

MONDO:0016698 Pathograph 14 Show in embeddings browser glioma

Ependymoma is a glial neoplasm of ependymal / radial-glial lineage that arises along the neuraxis — in the supratentorial brain, the posterior fossa, or the spinal cord. It accounts for roughly 2-3% of primary CNS tumors in adults and up to 10% in children, and is one of the more common pediatric brain tumors. Its defining biological feature is that, unlike most adult gliomas, it carries very few recurrent point mutations; instead it is driven by compartment-specific fusion oncogenes and epigenetic reprogramming. Under the 5th edition of the WHO Classification of Tumours of the Central Nervous System (WHO CNS5, 2021), ependymal tumors are therefore classified first by anatomical compartment and then by molecular group, because methylome profiling showed that compartment-specific groups are biologically distinct. Supratentorial tumors are defined by ZFTA (formerly C11orf95) or YAP1 fusions; posterior fossa tumors are split into group A (PFA) and group B (PFB) by methylation class or the H3 K27me3 immunohistochemical surrogate; spinal tumors are frequently defined by NF2 loss, except for an aggressive MYCN-amplified class. WHO CNS5 dropped the classic-versus-anaplastic distinction because tumor grade correlated poorly with survival. Histologically, ependymomas are recognized by perivascular pseudorosettes and, less commonly, true ependymal rosettes. Clinical presentation depends on location: posterior fossa tumors obstruct cerebrospinal fluid pathways and cause hydrocephalus, supratentorial tumors present with seizures or focal deficits, and spinal tumors cause back pain and sensorimotor deficits. Maximal safe surgical resection is the cornerstone of treatment, followed by focal conformal radiotherapy for most grade 2 and 3 tumors; cytotoxic chemotherapy has no established role as primary therapy. Extent of resection and molecular group are the strongest prognostic determinants.

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1
Inheritance
14
Pathophys.
2
Histopath.
12
Phenotypes
14
Pathograph
9
Genes
6
Medical Actions
8
Subtypes
1
Models
1
Deep Research
🏷

Classifications

ICD-O Morphology
Glioma
Harrison's Part
ONCOLOGY HEMATOLOGY
👪

Inheritance

1
Autosomal Dominant HP:0000006
Most ependymomas are sporadic. The principal hereditary predisposition is NF2-related schwannomatosis (formerly neurofibromatosis type 2), an autosomal dominant tumor-predisposition syndrome caused by germline NF2 mutation on chromosome 22, in which spinal ependymomas are a common tumor. Fifty to sixty percent of patients represent de novo mutations and up to a third of those are mosaic, which complicates genetic testing and counseling.
autosomal dominant inheritance
Show evidence (2 references)
PMID:23931824 SUPPORT Human Clinical
"Neurofibromatosis type 2 (NF2) is an autosomal dominant inherited tumor predisposition syndrome caused by mutations in the NF2 gene on chromosome 22."
Establishes the autosomal dominant inheritance and genetic basis of the predisposition syndrome.
PMID:23931824 SUPPORT Human Clinical
"Cranial and spinal meningiomas and spinal ependymomas are other common tumors."
Documents spinal ependymoma as a common tumor in NF2-related schwannomatosis.
◆

Subtypes

8
Supratentorial ependymoma, ZFTA fusion-positive
Supratentorial ependymoma defined by fusion of ZFTA (formerly C11orf95), most often to RELA. Under cIMPACT-NOW update 7 and WHO CNS5 the former "ependymoma, RELA fusion-positive" was renamed to reflect that ZFTA fusions with or without RELA involvement represent the same histomolecular entity.
Show evidence (1 reference)
PMID:36534422 SUPPORT Human Clinical
"Concerning supratentorial ependymomas, the previous RELA fusion-positive ependymoma has been renamed into ZFTA fusion-positive and the novel YAP1 fusion-positive ependymoma subtype has been added."
Confirms the WHO CNS5 renaming of the supratentorial ZFTA fusion-positive subtype.
Supratentorial ependymoma, YAP1 fusion-positive
Supratentorial ependymoma defined by YAP1 fusion, added as a distinct subtype in WHO CNS5. YAP1-fused tumors were among the two prototypic supratentorial fusion-defined molecular subgroups identified by methylation profiling.
Show evidence (1 reference)
PMID:25965575 SUPPORT Human Clinical
"Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively."
Identifies YAP1 fusion as defining one of the two supratentorial molecular subgroups.
Posterior fossa ependymoma, group A
Posterior fossa ependymoma of methylation group A, mainly diagnosed in infants and young children and carrying a poor prognosis. PFA tumors are characterized by a lack of the repressive H3K27me3 mark and high EZHIP expression; loss of H3 K27me3 by immunohistochemistry serves as a practical diagnostic surrogate.
Show evidence (2 references)
PMID:30923826 SUPPORT Human Clinical
"PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis, and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark."
Establishes the age distribution, prognosis and defining epigenetic mark loss of PFA ependymoma.
PMID:36534422 SUPPORT Human Clinical
"Posterior fossa ependymomas should now be allocated either to the Type A or Type B subtypes based on molecular profiling or using the H3 K27me3 immunohistochemical surrogate."
Establishes PFA/PFB assignment by methylation profiling or the H3 K27me3 immunohistochemical surrogate.
Posterior fossa ependymoma, group B
Posterior fossa ependymoma of methylation group B, occurring in older children and adults and carrying a substantially better prognosis than PFA. PFB tumors retain H3K27me3 immunoreactivity.
Show evidence (1 reference)
PMID:32502305 SUPPORT Human Clinical
"Common recurrent genetic or epigenetic alterations found in tumors belonging to the main molecular groups have been used to define tumor types at intracranial sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types of posterior fossa ependymoma defined by methylation group,..."
Defines PFA and PFB as the two methylation-defined posterior fossa ependymoma types.
Spinal ependymoma
Conventional spinal cord ependymoma, the most common intramedullary neoplasm in children and adults, carrying a better prognosis than intracranial disease. Loss of chromosome 22q and NF2 mutation are the only known recurrent genetic events in this methylation class.
Show evidence (2 references)
PMID:35384591 SUPPORT Human Clinical
"Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis."
Contrasts the frequency and prognosis of spinal versus intracranial ependymoma.
PMID:38265489 SUPPORT Human Clinical
"The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations"
Identifies 22q loss and NF2 mutation as the recurrent genetic events defining the spinal ependymoma methylation class.
Spinal ependymoma, MYCN-amplified
Aggressive spinal ependymoma type defined by MYCN amplification, added in WHO CNS5. These tumors are prone to infiltration of the spinal cord and dissemination through the CNS, and outcome remains poor.
Show evidence (1 reference)
PMID:31414211 SUPPORT Human Clinical
"Copy number variation plots derived from DNA methylation arrays showed MYCN amplification as a characteristic genetic alteration in all cases of our cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization."
Establishes MYCN amplification as the defining alteration of this spinal ependymoma subgroup.
Myxopapillary ependymoma
Histopathologically defined ependymal tumor type arising almost exclusively in the region of the conus medullaris, cauda equina and filum terminale. WHO CNS5 assigns it grade 2, a change from its previous grade 1 designation.
Show evidence (1 reference)
PMID:32502305 SUPPORT Human Clinical
"Myxopapillary ependymoma and subependymoma have been retained as histopathologically defined tumor types, but the classification has dropped the distinction between classic and anaplastic ependymoma."
Confirms myxopapillary ependymoma is retained as a histopathologically defined type.
Subependymoma
Slow-growing, histopathologically defined WHO grade 1 ependymal tumor, typically intraventricular and often an incidental finding. Retained as a distinct type in the molecular era because it is defined by histopathology rather than by a recurrent molecular alteration.
Show evidence (1 reference)
PMID:27022130 SUPPORT Human Clinical
"Myxopapillary ependymomas and subependymomas have different biology than ependymomas with typical WHO grade II or III histology."
Distinguishes subependymoma biology from conventional grade 2-3 ependymoma.
⚙

Pathophysiology

14
Radial Glial Progenitor Transformation
Ependymal neoplasms arise from the progenitors of the cells lining the ventricular system and spinal central canal. Radial glia are the proposed cell of origin, and compartment-restricted progenitor populations explain why supratentorial, posterior fossa and spinal ependymomas are molecularly distinct despite similar histology.
radial glial cell CL:0000681 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves radial glial cell (CL:0000681). CL:0000681 is a cell type from the Cell Ontology. ependymal cell CL:0000065 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ependymal cell (CL:0000065). CL:0000065 is a cell type from the Cell Ontology.
ventricular system of brain UBERON:0005282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ventricular system of brain (UBERON:0005282). UBERON:0005282 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
ZFTA-RELA Fusion Formation Supratentorial neural stem cells transformed by ZFTA-RELA fusion give rise to supratentorial ependymoma.
EZHIP Overexpression Hindbrain progenitors give rise to PFA ependymoma, which is defined by ectopic EZHIP overexpression.
CpG Island Methylator Phenotype Silencing Hindbrain progenitors in poor-prognosis PFA tumors acquire a CpG island methylator phenotype.
Impaired Lineage Differentiation Transformed progenitors fail to complete neuronal-glial differentiation, establishing a tumor cellular hierarchy.
Show evidence (2 references)
PMID:17179988 SUPPORT Other
"radial glia are cells of origin of ependymoma"
Review of the evidence identifying radial glia as the cell of origin of ependymoma.
PMID:36534422 SUPPORT Human Clinical
"Ependymal neoplasms are a heterogenous group of neoplasms arising from the progenitors of the cells lining the ventricular system and the spinal central canal."
Identifies progenitors of ependymal lining cells as the origin of ependymal neoplasms.
Impaired Lineage Differentiation
Single-cell RNA sequencing shows that ependymomas are organized as a cellular hierarchy initiating from undifferentiated populations that undergo impaired differentiation toward three neuronal-glial lineages. The proportion of undifferentiated cells tracks with aggressiveness: favorable molecular groups are dominated by differentiated cells, whereas aggressive groups are enriched for undifferentiated populations.
neural stem cell CL:0000047 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neural stem cell (CL:0000047). CL:0000047 is a cell type from the Cell Ontology.
cell differentiation GO:0030154 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cell differentiation (GO:0030154). GO:0030154 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Uncontrolled Tumor Cell Proliferation Retention of undifferentiated progenitor populations sustains tumor growth.
Show evidence (2 references)
PMID:32663469 SUPPORT Human Clinical
"Ependymomas are composed of a cellular hierarchy initiating from undifferentiated populations, which undergo impaired differentiation toward three lineages of neuronal-glial fate specification."
Establishes the differentiation-blocked cellular hierarchy underlying ependymoma.
PMID:32663469 SUPPORT Human Clinical
"While prognostically favorable groups of ependymoma predominantly harbor differentiated cells, aggressive groups are enriched for undifferentiated cell populations."
Links the degree of differentiation block to prognosis across molecular groups.
ZFTA-RELA Fusion Formation
The majority of supratentorial ependymomas harbor oncogenic fusions between RELA, the principal effector of canonical NF-kB signalling, and ZFTA (formerly C11orf95). These fusions arise by chromothripsis of chromosome 11q13.1 — a single catastrophic chromosomal shattering and reassembly event rather than stepwise mutation. This explains how a tumor with an otherwise very low mutation burden acquires a potent driver.
chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ⚠ ABNORMAL
lateral ventricle UBERON:0002285 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lateral ventricle, annotated with telencephalic ventricle (UBERON:0002285). UBERON:0002285 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Constitutive NF-kB Pathway Activation The fusion protein translocates to the nucleus and activates NF-kB target genes.
Show evidence (2 references)
PMID:24553141 SUPPORT Human Clinical
"Here we show that more than two-thirds of supratentorial ependymomas contain oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling, and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1."
Establishes the frequency of the fusion in supratentorial ependymoma and chromothripsis as its mechanism of formation.
PMID:29949764 SUPPORT Model Organism
"The majority of supratentorial ependymomas (ST-ependymomas) have few mutations but frequently display chromothripsis of chromosome 11q that generates a fusion between C11orf95 and RELA"
Independently confirms the low mutation burden and chromothripsis-generated fusion in supratentorial ependymoma.
Constitutive NF-kB Pathway Activation
ZFTA-RELA fusion proteins localize spontaneously to the nucleus and constitutively activate canonical NF-kB target gene transcription, independently of upstream inflammatory signalling. This is a rare example of a recurrent genetic lesion directly activating NF-kB in human cancer, since constitutive NF-kB signalling is common in tumors but pathway mutations are otherwise rare. Mouse modelling indicates that additional driver functions beyond NF-kB contribute to tumorigenesis.
canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased canonical NF-kappaB signal transduction (GO:0007249). GO:0007249 is a biological process from the Gene Ontology. ↑ INCREASED regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Uncontrolled Tumor Cell Proliferation NF-kB target gene programs drive proliferation and survival of transformed progenitors.
Show evidence (1 reference)
PMID:24553141 SUPPORT Human Clinical
"Although constitutive NF-κB signalling is present in most human tumours, mutations in pathway members are rare, complicating efforts to understand and block aberrant NF-κB activity in cancer."
Frames the ZFTA-RELA fusion as an unusual recurrent genetic activator of NF-kB, motivating its role as a driver lesion.
EZHIP Overexpression
Posterior fossa type A ependymomas overexpress EZHIP (also called CXorf67). Overexpression, not mutation, is the lesion: EZHIP is a normally germline-restricted protein whose ectopic expression in hindbrain progenitors is the hallmark of the PFA methylation class.
fourth ventricle UBERON:0002422 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in fourth ventricle (UBERON:0002422). UBERON:0002422 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
PRC2 Catalytic Inhibition EZHIP protein binds and inhibits the PRC2 catalytic subunit EZH2.
Show evidence (1 reference)
PMID:30923826 SUPPORT Human Clinical
"Recently, we reported overexpression of chromosome X open reading frame 67 (CXorf67) as a hallmark of PFA ependymoma"
Establishes EZHIP/CXorf67 overexpression as the hallmark lesion of PFA ependymoma, reported in human PFA tumor cohorts.
PRC2 Catalytic Inhibition
A short, highly conserved C-terminal peptide of EZHIP mimics the sequence of K27M-mutated histones and contacts the active site of the EZH2 subunit, blocking PRC2 methyltransferase activity. EZHIP therefore acts as an "oncohistone mimic", producing the same functional lesion as the H3 K27M mutation of diffuse midline glioma without any histone mutation.
facultative heterochromatin formation GO:0140718 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased facultative heterochromatin formation (GO:0140718). GO:0140718 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Global H3K27me3 Loss Loss of PRC2 catalytic activity prevents deposition and spreading of the H3K27me3 mark.
Show evidence (1 reference)
PMID:31086175 SUPPORT In Vitro
"Here we find that a conserved sequence in EZHIP is necessary and sufficient to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone."
Establishes the biochemical mechanism by which EZHIP inhibits PRC2 catalysis.
Global H3K27me3 Loss
PFA ependymomas are characterized by global depletion of the repressive H3K27me3 mark, with loss of broad domains but retention at CpG islands. The resulting de-repression of PRC2 target genes is the defining epigenetic lesion of the group and is used diagnostically as an immunohistochemical surrogate.
negative regulation of gene expression, epigenetic GO:0045814 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of gene expression, epigenetic (GO:0045814). GO:0045814 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Impaired Lineage Differentiation De-repression of PRC2 target neurodevelopmental genes prevents orderly lineage maturation.
Show evidence (1 reference)
PMID:30923826 SUPPORT Human Clinical
"PFA tumors are mainly diagnosed in infants and young children, show a poor prognosis, and are characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark."
Documents global H3K27me3 loss as the defining feature of PFA tumors.
CpG Island Methylator Phenotype Silencing
Poor-prognosis hindbrain ependymomas independently exhibit a CpG island methylator phenotype (CIMP). Transcriptional silencing driven by CpG methylation converges on the same Polycomb repressive complex 2 targets, reinforcing the differentiation block. This epigenetic program, rather than recurrent point mutation, drives tumorigenesis — these tumors have an extremely low mutation rate with no significant recurrent somatic single nucleotide variants.
negative regulation of gene expression, epigenetic GO:0045814 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated negative regulation of gene expression, epigenetic (GO:0045814). GO:0045814 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Impaired Lineage Differentiation De-repression and dysregulation of PRC2 target differentiation genes blocks normal lineage maturation.
Uncontrolled Tumor Cell Proliferation Failure to silence differentiation programs maintains progenitors in a proliferative state.
Show evidence (2 references)
PMID:24553142 SUPPORT Human Clinical
"Transcriptional silencing driven by CpG methylation converges exclusively on targets of the Polycomb repressive complex 2 which represses expression of differentiation genes through trimethylation of H3K27."
Establishes convergence of CIMP-driven silencing on PRC2 targets in poor-prognosis hindbrain ependymoma.
PMID:24553142 SUPPORT Human Clinical
"Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals an extremely low mutation rate, and zero significant recurrent somatic single nucleotide variants."
Documents the very low mutational burden, supporting an epigenetic rather than mutational driver mechanism.
NF2 Loss in Spinal Ependymoma
Classic spinal ependymoma is characterized by biallelic inactivation of the NF2 tumor suppressor on chromosome 22q, arising from a germline or somatic NF2 mutation combined with loss of chromosome 22q. NF2 encodes merlin, a membrane-cytoskeleton scaffold that restrains growth signalling; its loss is the only recurrent genetic event in this methylation class.
spinal cord UBERON:0002240 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spinal cord (UBERON:0002240). UBERON:0002240 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Uncontrolled Tumor Cell Proliferation Loss of merlin-mediated growth suppression permits progenitor expansion.
Show evidence (1 reference)
PMID:38265489 SUPPORT Human Clinical
"The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations"
Establishes 22q loss and NF2 mutation as the recurrent genetic events in spinal ependymoma.
MYCN Amplification in Spinal Ependymoma
A rare spinal ependymal tumor subgroup identified by DNA methylation profiling carries MYCN amplification in all reported cases. MYCN amplification drives an aggressive phenotype with spinal cord infiltration and CNS dissemination, in contrast to the generally good prognosis of other spinal ependymal tumors.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
spinal cord UBERON:0002240 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in spinal cord (UBERON:0002240). UBERON:0002240 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
CNS Dissemination MYCN-amplified spinal tumors infiltrate the spinal cord and disseminate through the CNS.
Show evidence (1 reference)
PMID:31414211 SUPPORT Human Clinical
"Here, we describe a new and relatively rare subgroup of spinal ependymal tumors identified using DNA methylation profiling that is distinct from other molecular subgroups of ependymoma."
Establishes MYCN-amplified spinal ependymoma as a distinct methylation-defined subgroup.
Uncontrolled Tumor Cell Proliferation
Convergent consequence of the compartment-specific driver lesions. Whether initiated by fusion-driven NF-kB transcription, PRC2 inhibition, NF2 loss, or MYCN amplification, transformed ependymal progenitors proliferate without normal growth restraint and form an expanding intraventricular or intramedullary mass.
ependymal cell CL:0000065 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ependymal cell (CL:0000065). CL:0000065 is a cell type from the Cell Ontology.
cell population proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Cerebrospinal Fluid Pathway Obstruction An enlarging posterior fossa or intraventricular mass obstructs CSF flow.
CNS Dissemination Tumor cells seed the leptomeninges via the cerebrospinal fluid.
Show evidence (1 reference)
PMID:32663469 SUPPORT Human Clinical
"aggressive groups are enriched for undifferentiated cell populations"
Associates the proliferative, undifferentiated cell compartment with the aggressive molecular groups, supporting unrestrained proliferation as the convergent outcome.
Cerebrospinal Fluid Pathway Obstruction
Posterior fossa ependymomas characteristically arise in or extend into the fourth ventricle, where they obstruct cerebrospinal fluid pathways. The resulting non-communicating hydrocephalus and raised intracranial pressure produce the classic presenting syndrome of headache, vomiting and papilledema.
fourth ventricle UBERON:0002422 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in fourth ventricle (UBERON:0002422). UBERON:0002422 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Raised Intracranial Pressure Syndrome Obstructed CSF outflow raises intracranial pressure.
Show evidence (1 reference)
PMID:40556668 SUPPORT Human Clinical
"Clinical symptoms vary by location, with posterior fossa tumors often causing hydrocephalus-related signs, and supratentorial lesions presenting with seizures or focal deficits."
Links posterior fossa location to hydrocephalus and supratentorial location to seizures and focal deficits.
Raised Intracranial Pressure Syndrome
Clinical endpoint of CSF obstruction: progressive hydrocephalus with headache, vomiting, papilledema and, in infants, macrocephaly and a bulging fontanelle. This is the dominant presenting syndrome for posterior fossa ependymoma and the reason urgent surgical decompression is frequently required.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:8677342 SUPPORT Human Clinical
"Signs and symptoms related to increased intracranial pressure are often reported and vary according to the patient's age."
Establishes the raised intracranial pressure syndrome and its age-dependent presentation in paediatric intracranial tumors.
CNS Dissemination
Ependymoma spreads through the cerebrospinal fluid rather than haematogenously. Leptomeningeal dissemination is present at diagnosis in up to 10% of intracranial cases, which is why staging includes craniospinal imaging and CSF cytology, and why craniospinal irradiation is reserved for documented metastatic disease.
ventricular system of brain UBERON:0005282 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ventricular system of brain (UBERON:0005282). UBERON:0005282 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:40556668 SUPPORT Human Clinical
"Diagnosis requires histologic confirmation, aided by MRI and cerebrospinal fluid analysis, with dissemination present in up to 10% of cases at diagnosis."
Quantifies the frequency of dissemination at diagnosis and the role of CSF analysis in staging.
✶

Histopathology

2
Perivascular Pseudorosettes
Tumor cells arranged radially around blood vessels with a perivascular anucleate fibrillary zone. This is the most consistent diagnostic histological feature of ependymoma across compartments and molecular groups, and is accompanied by GFAP and EMA positivity.
Show evidence (1 reference)
PMID:31414211 SUPPORT Human Clinical
"Histological re-evaluation in five primary tumors and seven relapses showed characteristic histological features of ependymoma, namely pseudorosettes, GFAP- and EMA positivity."
Identifies pseudorosettes together with GFAP and EMA positivity as the characteristic histological features of ependymoma.
Ependymal Rosettes
True ependymal rosettes — tumor cells arranged around a central lumen recapitulating the ependymal canal — are highly specific for ependymoma but much less frequent than perivascular pseudorosettes.
Show evidence (1 reference)
PMID:11211057 SUPPORT Human Clinical
"forming true ependymal rosettes and perivascular pseudorosettes with fibrillary background"
Describes true ependymal rosettes occurring alongside perivascular pseudorosettes in a histologically confirmed ependymoma.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Ependymoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Digestive 1
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013). HP:0002013 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40556668 SUPPORT Human Clinical
"nausea, vomiting, ataxia, vertigo, and papilledema"
Ependymoma-specific source listing this sign among the presenting features of posterior fossa ependymoma with obstructive hydrocephalus.
PMID:8677342 SUPPORT Human Clinical
"Macrocrania and a bulging fontanel can be observed in infants and toddlers, whereas headache, papilledema and vomiting are present in the older children."
Documents the age-dependent signs of raised intracranial pressure in paediatric intracranial tumors, the mechanism by which this feature arises in ependymoma.
Eye 1
Papilledema HP:0001085 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Papilledema (HP:0001085). HP:0001085 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:40556668 SUPPORT Human Clinical
"nausea, vomiting, ataxia, vertigo, and papilledema"
Ependymoma-specific source listing this sign among the presenting features of posterior fossa ependymoma with obstructive hydrocephalus.
PMID:8677342 SUPPORT Human Clinical
"Macrocrania and a bulging fontanel can be observed in infants and toddlers, whereas headache, papilledema and vomiting are present in the older children."
Documents the age-dependent signs of raised intracranial pressure in paediatric intracranial tumors, the mechanism by which this feature arises in ependymoma.
Head and Neck 1
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8677342 SUPPORT Human Clinical
"Macrocrania and a bulging fontanel can be observed in infants and toddlers, whereas headache, papilledema and vomiting are present in the older children."
Documents the age-dependent signs of raised intracranial pressure in paediatric intracranial tumors, the mechanism by which this feature arises in ependymoma.
Musculoskeletal 1
Muscle Weakness FREQUENT HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38074692 SUPPORT Human Clinical
"are the most common (58%), followed by weakness (45%), back pain (35%), and radiating back pain (27%)"
Gives the frequency of weakness (45%) among presenting symptoms of adult spinal ependymoma, supporting both the association and the FREQUENT band.
Nervous System 5
Hydrocephalus HP:0000238 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrocephalus (HP:0000238). HP:0000238 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40556668 SUPPORT Human Clinical
"Clinical symptoms vary by location, with posterior fossa tumors often causing hydrocephalus-related signs, and supratentorial lesions presenting with seizures or focal deficits."
Directly associates posterior fossa ependymoma with hydrocephalus-related clinical signs.
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315), qualified as temporality prolonged. HP:0002315 is a phenotype from the Human Phenotype Ontology.
Temporal: PROLONGED
Show evidence (1 reference)
PMID:8677342 SUPPORT Human Clinical
"Macrocrania and a bulging fontanel can be observed in infants and toddlers, whereas headache, papilledema and vomiting are present in the older children."
Documents the age-dependent signs of raised intracranial pressure in paediatric intracranial tumors, the mechanism by which this feature arises in ependymoma.
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40556668 SUPPORT Human Clinical
"Clinical symptoms vary by location, with posterior fossa tumors often causing hydrocephalus-related signs, and supratentorial lesions presenting with seizures or focal deficits."
Associates supratentorial ependymoma specifically with seizures.
Ataxia HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40556668 SUPPORT Human Clinical
"nausea, vomiting, ataxia, vertigo, and papilledema"
Lists ataxia among the presenting features of posterior fossa ependymoma with obstructive hydrocephalus.
Dysesthesia FREQUENT HP:0012534 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysesthesia (HP:0012534). HP:0012534 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38074692 SUPPORT Human Clinical
"are the most common (58%), followed by weakness (45%)"
Gives the frequency of dysesthesia (58%, the most common presenting symptom) in adult spinal ependymoma, supporting both the association and the FREQUENT band.
Constitutional 2
Back Pain FREQUENT HP:0003418 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Back pain (HP:0003418). HP:0003418 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38074692 SUPPORT Human Clinical
"are the most common (58%), followed by weakness (45%), back pain (35%), and radiating back pain (27%)"
Gives the frequency of back pain (35%) among presenting symptoms of adult spinal ependymoma, supporting both the association and the FREQUENT band.
Urinary Sphincter Dysfunction Urinary incontinence HP:0000020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is urinary incontinence (HP:0000020). HP:0000020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38074692 SUPPORT Human Clinical
"limb weakness, and sphincter dysfunction"
Lists sphincter dysfunction among the common symptoms of anaplastic spinal ependymoma.
Other 1
Cranial Nerve Palsy FREQUENT Abnormal cranial nerve physiology HP:0031910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is cranial nerve palsy, annotated with Abnormal cranial nerve physiology (HP:0031910). HP:0031910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40556668 SUPPORT Human Clinical
"Cranial nerve palsies — particularly of nerves VI to X — are frequent"
Establishes cranial nerve palsy as a frequent feature of posterior fossa ependymoma.
🧬

Genetic Associations

9
ZFTA (Fusion)
Show evidence (1 reference)
PMID:34389065 SUPPORT Human Clinical
"This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity."
Confirms ZFTA fusions with or without RELA define a single histomolecular entity.
RELA (Fusion)
Show evidence (1 reference)
PMID:24553141 SUPPORT Human Clinical
"Our data identify a highly recurrent genetic alteration of RELA in human cancer"
Establishes RELA fusion as a highly recurrent genetic alteration in this tumor.
YAP1 (Fusion)
Show evidence (1 reference)
PMID:25965575 SUPPORT Human Clinical
"Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively."
Identifies YAP1 fusion as defining a distinct supratentorial molecular subgroup.
EZHIP (Overexpression)
Show evidence (1 reference)
PMID:31086175 SUPPORT In Vitro
"Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67)."
Documents EZHIP overexpression and low H3K27 methylation as features of PFA ependymoma.
NF2 (Loss of Function)
Show evidence (1 reference)
PMID:38265489 SUPPORT Human Clinical
"The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations"
Establishes NF2 mutation and 22q loss as the recurrent genetic events in spinal ependymoma.
MYCN (Amplification)
Show evidence (1 reference)
PMID:31414211 SUPPORT Human Clinical
"The histological diagnosis was anaplastic ependymoma (WHO Grade III) in ten cases and classic ependymoma (WHO Grade II) in three cases."
Documents the histological grade distribution of MYCN-amplified spinal ependymoma.
Chromosome 1q (Gain)
Show evidence (1 reference)
PMID:16609018 SUPPORT Human Clinical
"gain of 1q25 as determined by fluorescence in situ hybridization represented an independent prognostic marker"
Establishes 1q25 gain as an independent prognostic marker in intracranial ependymoma, supporting the adverse-biomarker claim.
CDKN2A (Homozygous Deletion)
Show evidence (1 reference)
PMID:20516456 SUPPORT Human Clinical
"age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised the most powerful independent indicators of unfavorable prognosis"
Directly identifies homozygous CDKN2A deletion as one of the most powerful independent adverse prognostic indicators in intracranial ependymoma.
EGFR (Overexpression)
Show evidence (1 reference)
PMID:16609018 SUPPORT Human Clinical
"EGFR protein status subdivides intracranial grade II ependymomas into two different risk groups"
Establishes EGFR protein overexpression as a prognostic stratifier in intracranial ependymoma.
💊

Medical Actions

6
Maximal Safe Surgical Resection
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Complete surgical resection is the single most important prognostic and therapeutic intervention across all ependymoma compartments and molecular groups. A complete resection should be attempted whenever possible, at first surgery or at reoperation.
Show evidence (1 reference)
PMID:35384591 SUPPORT Human Clinical
"The majority of studies have shown a major impact of extent of resection; thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation."
Establishes extent of resection as the dominant modifiable prognostic factor and complete resection as the surgical goal.
Conformal Radiation Therapy
Action: radiation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is radiation therapy (NCIT:C15313). NCIT:C15313 is a clinical intervention from the NCI Thesaurus. Ontology label: Radiation Therapy NCIT:C15313
Focal conformal radiotherapy is recommended for grade 3 tumors and for incompletely resected grade 2 tumors. In the Children's Oncology Group ACNS0121 trial, immediate postoperative conformal radiation therapy was delivered to a cumulative dose of 59.4 Gy with a 1.0-cm clinical target volume margin.
Show evidence (2 references)
PMID:35384591 SUPPORT Human Clinical
"Conformal radiotherapy is recommended for grade 3 or incompletely resected grade II tumors."
States the indication for conformal radiotherapy by grade and extent of resection.
PMID:30811284 SUPPORT Human Clinical
"CRT was administered with a 1.0-cm clinical target volume margin. The cumulative total dose was 59.4 Gy"
Documents the conformal radiotherapy dose and margin used in the ACNS0121 cooperative group trial.
Proton Beam Radiation Therapy
Action: proton beam radiation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is proton beam radiation therapy (NCIT:C66897). NCIT:C66897 is a clinical intervention from the NCI Thesaurus. Ontology label: Proton Beam Radiation Therapy NCIT:C66897
Proton therapy is increasingly used, especially in children, to reduce the dose delivered to developing normal brain and thereby lower the risk of neurocognitive and endocrine late effects.
Show evidence (1 reference)
PMID:35384591 SUPPORT Human Clinical
"Proton therapy is increasingly employed especially in children to reduce the risk of neurocognitive and endocrine sequelae."
States the rationale and paediatric preference for proton therapy.
Craniospinal Irradiation
Action: craniospinal irradiationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is craniospinal irradiation (NCIT:C116437). NCIT:C116437 is a clinical intervention from the NCI Thesaurus. Ontology label: Craniospinal Irradiation NCIT:C116437
Craniospinal irradiation is reserved for documented metastatic (leptomeningeal) disease rather than being used routinely, because of its substantial neurocognitive and growth toxicity.
Show evidence (1 reference)
PMID:35384591 SUPPORT Human Clinical
"Craniospinal irradiation is reserved for metastatic disease."
Defines metastatic disease as the indication for craniospinal irradiation.
Salvage Chemotherapy
Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Cytotoxic chemotherapy has no established role as primary therapy for ependymoma and does not improve survival when added to surgery and radiation. It is used as salvage treatment for patients failing surgery and radiotherapy, and to delay irradiation in infants or after subtotal resection.
Show evidence (2 references)
PMID:35384591 SUPPORT Human Clinical
"Chemotherapy is not useful as primary treatment and is commonly employed as salvage treatment for patients failing surgery and radiotherapy."
Establishes that chemotherapy is a salvage rather than primary modality.
PMID:24553142 SUPPORT Human Clinical
"Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival."
Confirms that cytotoxic chemotherapy does not add a survival benefit to surgery and radiation.
Locoregional CAR T-Cell Therapy
Action: chimeric antigen receptor T-cell therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chimeric antigen receptor T-cell therapy (NCIT:C126102). NCIT:C126102 is a clinical intervention from the NCI Thesaurus. Ontology label: Chimeric Antigen Receptor T-Cell Therapy NCIT:C126102
Experimental, not standard of care. Because PFA ependymomas and their recurrences sit adjacent to and are bathed by cerebrospinal fluid, intrathecal delivery of chimeric antigen receptor T cells against EPHA2, HER2 and IL13Rα2 bypasses the blood-brain barrier. Validated to date only in mouse xenograft models.
Show evidence (1 reference)
PMID:32341580 SUPPORT Model Organism
"We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models."
Preclinical mouse-xenograft evidence for intrathecal CAR T-cell therapy in PFA ependymoma; not yet clinically established.
🌍

Environmental Factors

1
High-dose ionizing radiation
High-dose ionizing radiation is the only established environmental risk factor for childhood CNS tumors including ependymoma. Investigations of other environmental aetiologies, including dietary N-nitroso compounds, have not produced consistent associations, and ependymoma is otherwise largely sporadic.
Show evidence (1 reference)
PMID:16142778 SUPPORT Human Clinical
"Whilst high dose ionising radiation is an established risk factor for this group of tumours, reported associations with dietary N-nitroso compounds have not been consistent"
Establishes high-dose ionizing radiation as the only confirmed environmental risk factor for childhood CNS tumors.
🔬

Diagnosis

4
DNA methylation array profiling
Genome-wide DNA methylation profiling is the reference method for assigning an ependymal tumor to its molecular group and is definitional for the WHO CNS5 types. It is not merely confirmatory: in a series of histopathologically diagnosed ependymoma variants, integrated diagnosis had to be revised in more than a third of cases once methylation class was taken into account.
methylation testing NCIT:C165222 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:31679042 SUPPORT Human Clinical
"Overall, integrated diagnosis had to be changed in 35.6% of cases as compared to the initial diagnosis."
Quantifies how often methylation profiling overturns a purely histopathological ependymoma diagnosis, establishing it as the reference method.
Surrogate immunohistochemistry for molecular group
Where methylation profiling is unavailable, immunohistochemistry serves as a practical surrogate: L1CAM for ZFTA fusion in supratentorial tumors, and loss of H3K27me3 or EZHIP overexpression for posterior fossa group A.
immunohistochemistry NCIT:C23020 NCI Thesaurus (NCIT)
Markers: L1CAM, H3K27me3, EZHIP
Show evidence (1 reference)
PMID:34812989 SUPPORT Human Clinical
"Surrogate IHC markers revealed high concordance rates between L1CAM and ZFTA-fusion and H3K27me3 loss or EZHIP overexpression was used for PFA-EPNs."
Validates L1CAM, H3K27me3 loss and EZHIP as immunohistochemical surrogates for the defining molecular alterations.
Ki-67 proliferation index
A Ki-67 labelling index with a 7% cut-off separates ependymomas into two prognostic grades across all anatomical compartments, and was the only independent prognostic factor in a 141-tumor reclassified cohort.
immunohistochemistry NCIT:C23020 NCI Thesaurus (NCIT)
Markers: Ki-67
Show evidence (1 reference)
PMID:34812989 SUPPORT Human Clinical
"The 7% cut-off of Ki-67 was sufficient to classify EPNs into two-tiered grades at all anatomical locations."
Establishes the Ki-67 7% cut-off as a grading and prognostic discriminator.
Diagnostic histology with MRI and CSF staging
Diagnosis requires histological confirmation showing perivascular pseudorosettes with GFAP and EMA positivity. MRI of brain and whole spine plus cerebrospinal fluid cytology stage leptomeningeal dissemination, which is present in up to 10% of intracranial cases at diagnosis and determines whether craniospinal irradiation is indicated.
magnetic resonance imaging procedure NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:40556668 SUPPORT Human Clinical
"Diagnosis requires histologic confirmation, aided by MRI and cerebrospinal fluid analysis, with dissemination present in up to 10% of cases at diagnosis."
Establishes the combined histological, MRI and CSF workup and its staging role.
📈

Progression

2
Presentation and primary therapy
Age: Median 5 years for intracranial disease; adults for spinal disease
Onset is typically subacute to chronic, culminating in a raised intracranial pressure crisis for posterior fossa tumors. Achieving gross total resection at the initial operation is the critical intervention window, since extent of resection is the dominant modifiable prognostic factor.
Show evidence (1 reference)
PMID:40556668 SUPPORT Human Clinical
"Maximal safe surgical resection is the cornerstone of treatment."
Identifies primary resection as the decisive therapeutic step at presentation.
Long-term outcome and recurrence
Recurrences are predominantly local rather than disseminated. Ten-year overall survival across all ependymoma ranges from 50% to 75% and is governed by extent of resection, molecular subtype and age; posterior fossa group B has an excellent outcome whereas group A with chromosome 1q gain does poorly.
Show evidence (1 reference)
PMID:40556668 SUPPORT Human Clinical
"Ten-year overall survival ranges from 50% to 75%, influenced by extent of resection, molecular subtype, and age."
Provides the long-term survival range and the factors that modify it.
🌍

Epidemiology

4
Proportion of primary CNS tumors
Ependymomas account for approximately 2-3% of primary CNS tumors in adults and up to 10% in children, making them one of the more common pediatric brain tumors.
Show evidence (1 reference)
PMID:30855832 SUPPORT Human Clinical
"They account for approximately 2% to 3% of all primary central nervous system (CNS) tumors in adults and up to 10% in children, making them one of the more common pediatric brain tumors after medulloblastoma and juvenile pilocytic astrocytoma."
Provides the proportion of primary CNS tumors represented by ependymoma in adults and children.
Population incidence
In combined CBTRUS/NPCR/SEER data, ependymoma had the highest average annual age-adjusted incidence rate among the 12 rare CNS tumor types tracked by NCI-CONNECT, at 0.41 per 100,000 population.
Show evidence (1 reference)
PMID:37980692 SUPPORT Human Clinical
"AAAIR was 1.47 per 100,000 for these tumors combined, with highest incidence in ependymomas (AAAIR = 0.41/100,000)."
Provides the population-based age-adjusted incidence rate for ependymoma from a national registry analysis.
Anatomic distribution by age
Anatomic distribution differs sharply by age: about two-thirds of pediatric ependymomas are intracranial and most often arise in the posterior fossa, whereas in adults most tumors are spinal.
Show evidence (1 reference)
PMID:30855832 SUPPORT Human Clinical
"These tumors demonstrate a wide anatomic distribution: approximately two-thirds occur intracranially in children, most often in the posterior fossa; in adults, most cases are located in the spinal cord."
Documents the age-dependent anatomic distribution of ependymoma.
Median age of intracranial disease
Intracranial ependymomas most commonly affect young children, with a median age of about 5 years, and show a slight male predominance. Ependymomas predominantly affect children under 10 years of age.
Show evidence (2 references)
PMID:40556668 SUPPORT Human Clinical
"Intracranial ependymomas are glial tumors arising from the ependymal lining of the ventricular system, most commonly affecting young children (median age: 5 years), though they can occur across all age groups."
Establishes median age at presentation and the predominance of young children among intracranial ependymomas.
PMID:16142778 SUPPORT Human Clinical
"ependymomas mainly occur in children less than 10 years"
Independent epidemiologic review confirming the paediatric age distribution of ependymoma.
🐁

Animal Models

1
C11orf95-RELA (ZFTA-RELA) fusion expressed in periventricular neural stem cells Mouse (Mus musculus) Transgenic
De novo mouse model in which the C11orf95-RELA fusion is introduced into periventricular neural stem cells, generating supratentorial ependymoma. The model established that the fusion is sufficient to drive tumorigenesis in vivo and identified driver functions beyond NF-kB signalling. Limitation: it models only the supratentorial ZFTA-fused compartment and does not recapitulate PFA biology, for which EZHIP is eutherian-specific.
Supratentorial ependymoma
Species
Mouse (Mus musculus)
Genotype
C11orf95-RELA (ZFTA-RELA) fusion expressed in periventricular neural stem cells
Genes
RELA hgnc:9955 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns RELA (hgnc:9955). hgnc:9955 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:29949764 SUPPORT Model Organism
"We show that RELAFUS drives ST-ependymoma formation from periventricular neural stem cells in mice"
Demonstrates that the fusion alone initiates supratentorial ependymoma from periventricular neural stem cells in vivo.
{ }

Source YAML

click to show 
name: Ependymoma
creation_date: '2026-07-28T16:00:00Z'
updated_date: '2026-07-28T16:00:00Z'
description: >-
  Ependymoma is a glial neoplasm of ependymal / radial-glial lineage that arises
  along the neuraxis — in the supratentorial brain, the posterior fossa, or the
  spinal cord. It accounts for roughly 2-3% of primary CNS tumors in adults and
  up to 10% in children, and is one of the more common pediatric brain tumors.
  Its defining biological feature is that, unlike most adult gliomas, it carries
  very few recurrent point mutations; instead it is driven by compartment-specific
  fusion oncogenes and epigenetic reprogramming. Under the 5th edition of the WHO
  Classification of Tumours of the Central Nervous System (WHO CNS5, 2021),
  ependymal tumors are therefore classified first by anatomical compartment and
  then by molecular group, because methylome profiling showed that
  compartment-specific groups are biologically distinct. Supratentorial tumors are
  defined by ZFTA (formerly C11orf95) or YAP1 fusions; posterior fossa tumors are
  split into group A (PFA) and group B (PFB) by methylation class or the H3 K27me3
  immunohistochemical surrogate; spinal tumors are frequently defined by NF2 loss,
  except for an aggressive MYCN-amplified class. WHO CNS5 dropped the
  classic-versus-anaplastic distinction because tumor grade correlated poorly with
  survival. Histologically, ependymomas are recognized by perivascular
  pseudorosettes and, less commonly, true ependymal rosettes. Clinical
  presentation depends on location: posterior fossa tumors obstruct cerebrospinal
  fluid pathways and cause hydrocephalus, supratentorial tumors present with
  seizures or focal deficits, and spinal tumors cause back pain and sensorimotor
  deficits. Maximal safe surgical resection is the cornerstone of treatment,
  followed by focal conformal radiotherapy for most grade 2 and 3 tumors;
  cytotoxic chemotherapy has no established role as primary therapy. Extent of
  resection and molecular group are the strongest prognostic determinants.
categories:
- Central Nervous System Neoplasm
- Glioma
- Pediatric Brain Tumor
- Molecularly Defined Tumor
parents:
- glioma
epidemiology:
- name: Proportion of primary CNS tumors
  description: >-
    Ependymomas account for approximately 2-3% of primary CNS tumors in adults and
    up to 10% in children, making them one of the more common pediatric brain
    tumors.
  evidence:
  - reference: PMID:30855832
    reference_title: Ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: They account for approximately 2% to 3% of all primary central nervous
      system (CNS) tumors in adults and up to 10% in children, making them one of
      the more common pediatric brain tumors after medulloblastoma and juvenile pilocytic
      astrocytoma.
    explanation: Provides the proportion of primary CNS tumors represented by ependymoma
      in adults and children.
- name: Population incidence
  description: >-
    In combined CBTRUS/NPCR/SEER data, ependymoma had the highest average annual
    age-adjusted incidence rate among the 12 rare CNS tumor types tracked by
    NCI-CONNECT, at 0.41 per 100,000 population.
  evidence:
  - reference: PMID:37980692
    reference_title: 'Capturing evolving definitions of 12 select rare CNS tumors: a
      timely report from CBTRUS and NCI-CONNECT.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: AAAIR was 1.47 per 100,000 for these tumors combined, with highest incidence
      in ependymomas (AAAIR = 0.41/100,000).
    explanation: Provides the population-based age-adjusted incidence rate for ependymoma
      from a national registry analysis.
- name: Anatomic distribution by age
  description: >-
    Anatomic distribution differs sharply by age: about two-thirds of pediatric
    ependymomas are intracranial and most often arise in the posterior fossa,
    whereas in adults most tumors are spinal.
  evidence:
  - reference: PMID:30855832
    reference_title: Ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'These tumors demonstrate a wide anatomic distribution: approximately
      two-thirds occur intracranially in children, most often in the posterior fossa;
      in adults, most cases are located in the spinal cord.'
    explanation: Documents the age-dependent anatomic distribution of ependymoma.
- name: Median age of intracranial disease
  description: >-
    Intracranial ependymomas most commonly affect young children, with a median
    age of about 5 years, and show a slight male predominance. Ependymomas
    predominantly affect children under 10 years of age.
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Intracranial ependymomas are glial tumors arising from the ependymal
      lining of the ventricular system, most commonly affecting young children (median
      age: 5 years), though they can occur across all age groups.'
    explanation: Establishes median age at presentation and the predominance of young
      children among intracranial ependymomas.
  - reference: PMID:16142778
    reference_title: 'Central nervous system tumours in children: epidemiology and risk
      factors.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: ependymomas mainly occur in children less than 10 years
    explanation: Independent epidemiologic review confirming the paediatric age distribution
      of ependymoma.
has_subtypes:
- name: ST-ZFTA
  display_name: Supratentorial ependymoma, ZFTA fusion-positive
  description: >-
    Supratentorial ependymoma defined by fusion of ZFTA (formerly C11orf95), most
    often to RELA. Under cIMPACT-NOW update 7 and WHO CNS5 the former
    "ependymoma, RELA fusion-positive" was renamed to reflect that ZFTA fusions
    with or without RELA involvement represent the same histomolecular entity.
  evidence:
  - reference: PMID:36534422
    reference_title: Ependymomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Concerning supratentorial ependymomas, the previous RELA fusion-positive
      ependymoma has been renamed into ZFTA fusion-positive and the novel YAP1 fusion-positive
      ependymoma subtype has been added.
    explanation: Confirms the WHO CNS5 renaming of the supratentorial ZFTA fusion-positive
      subtype.
- name: ST-YAP1
  display_name: Supratentorial ependymoma, YAP1 fusion-positive
  description: >-
    Supratentorial ependymoma defined by YAP1 fusion, added as a distinct subtype
    in WHO CNS5. YAP1-fused tumors were among the two prototypic supratentorial
    fusion-defined molecular subgroups identified by methylation profiling.
  evidence:
  - reference: PMID:25965575
    reference_title: Molecular Classification of Ependymal Tumors across All CNS Compartments,
      Histopathological Grades, and Age Groups.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two supratentorial subgroups are characterized by prototypic fusion genes
      involving RELA and YAP1, respectively.
    explanation: Identifies YAP1 fusion as defining one of the two supratentorial molecular
      subgroups.
- name: PFA
  display_name: Posterior fossa ependymoma, group A
  description: >-
    Posterior fossa ependymoma of methylation group A, mainly diagnosed in infants
    and young children and carrying a poor prognosis. PFA tumors are characterized
    by a lack of the repressive H3K27me3 mark and high EZHIP expression; loss of
    H3 K27me3 by immunohistochemistry serves as a practical diagnostic surrogate.
  evidence:
  - reference: PMID:30923826
    reference_title: EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as
      an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PFA tumors are mainly diagnosed in infants and young children, show a poor
      prognosis, and are characterized by a lack of the repressive histone H3 lysine
      27 trimethylation (H3K27me3) mark.
    explanation: Establishes the age distribution, prognosis and defining epigenetic mark
      loss of PFA ependymoma.
  - reference: PMID:36534422
    reference_title: Ependymomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Posterior fossa ependymomas should now be allocated either to the Type
      A or Type B subtypes based on molecular profiling or using the H3 K27me3 immunohistochemical
      surrogate.
    explanation: Establishes PFA/PFB assignment by methylation profiling or the H3 K27me3
      immunohistochemical surrogate.
- name: PFB
  display_name: Posterior fossa ependymoma, group B
  description: >-
    Posterior fossa ependymoma of methylation group B, occurring in older
    children and adults and carrying a substantially better prognosis than PFA.
    PFB tumors retain H3K27me3 immunoreactivity.
  evidence:
  - reference: PMID:32502305
    reference_title: 'cIMPACT-NOW update 7: advancing the molecular classification of
      ependymal tumors.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Common recurrent genetic or epigenetic alterations found in tumors belonging
      to the main molecular groups have been used to define tumor types at intracranial
      sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types
      of posterior fossa ependymoma defined by methylation group, PFA and PFB.
    explanation: Defines PFA and PFB as the two methylation-defined posterior fossa
      ependymoma types.
- name: SP-EPN
  display_name: Spinal ependymoma
  description: >-
    Conventional spinal cord ependymoma, the most common intramedullary neoplasm
    in children and adults, carrying a better prognosis than intracranial disease.
    Loss of chromosome 22q and NF2 mutation are the only known recurrent genetic
    events in this methylation class.
  evidence:
  - reference: PMID:35384591
    reference_title: 'Ependymoma: Evaluation and Management Updates.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Compared with intracranial ependymomas, spinal ependymomas are less frequent
      and exhibit a better prognosis.
    explanation: Contrasts the frequency and prognosis of spinal versus intracranial
      ependymoma.
  - reference: PMID:38265489
    reference_title: Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN)
      identifies clinically relevant subtypes enriched for tumors with and without NF2
      mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The only known recurrent genetic events in SP-EPN are loss of chromosome
      22q and NF2 mutations
    explanation: Identifies 22q loss and NF2 mutation as the recurrent genetic events
      defining the spinal ependymoma methylation class.
- name: SP-MYCN
  display_name: Spinal ependymoma, MYCN-amplified
  description: >-
    Aggressive spinal ependymoma type defined by MYCN amplification, added in WHO
    CNS5. These tumors are prone to infiltration of the spinal cord and
    dissemination through the CNS, and outcome remains poor.
  evidence:
  - reference: PMID:31414211
    reference_title: MYCN amplification drives an aggressive form of spinal ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Copy number variation plots derived from DNA methylation arrays showed
      MYCN amplification as a characteristic genetic alteration in all cases of our
      cohort (n = 13), which was subsequently validated using fluorescence in situ hybridization.
    explanation: Establishes MYCN amplification as the defining alteration of this spinal
      ependymoma subgroup.
- name: Myxopapillary
  display_name: Myxopapillary ependymoma
  description: >-
    Histopathologically defined ependymal tumor type arising almost exclusively
    in the region of the conus medullaris, cauda equina and filum terminale. WHO
    CNS5 assigns it grade 2, a change from its previous grade 1 designation.
  evidence:
  - reference: PMID:32502305
    reference_title: 'cIMPACT-NOW update 7: advancing the molecular classification of
      ependymal tumors.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Myxopapillary ependymoma and subependymoma have been retained as histopathologically
      defined tumor types, but the classification has dropped the distinction between
      classic and anaplastic ependymoma.
    explanation: Confirms myxopapillary ependymoma is retained as a histopathologically
      defined type.
- name: Subependymoma
  display_name: Subependymoma
  description: >-
    Slow-growing, histopathologically defined WHO grade 1 ependymal tumor,
    typically intraventricular and often an incidental finding. Retained as a
    distinct type in the molecular era because it is defined by histopathology
    rather than by a recurrent molecular alteration.
  evidence:
  - reference: PMID:27022130
    reference_title: Biology and management of ependymomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Myxopapillary ependymomas and subependymomas have different biology than
      ependymomas with typical WHO grade II or III histology.
    explanation: Distinguishes subependymoma biology from conventional grade 2-3 ependymoma.
pathophysiology:
- name: Radial Glial Progenitor Transformation
  description: >-
    Ependymal neoplasms arise from the progenitors of the cells lining the
    ventricular system and spinal central canal. Radial glia are the proposed cell
    of origin, and compartment-restricted progenitor populations explain why
    supratentorial, posterior fossa and spinal ependymomas are molecularly
    distinct despite similar histology.
  cell_types:
  - preferred_term: radial glial cell
    term:
      id: CL:0000681
      label: radial glial cell
  - preferred_term: ependymal cell
    term:
      id: CL:0000065
      label: ependymal cell
  locations:
  - preferred_term: ventricular system of brain
    term:
      id: UBERON:0005282
      label: ventricular system of brain
  evidence:
  - reference: PMID:17179988
    reference_title: Stem cells of ependymoma.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: radial glia are cells of origin of ependymoma
    explanation: Review of the evidence identifying radial glia as the cell of origin of
      ependymoma.
  - reference: PMID:36534422
    reference_title: Ependymomas.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ependymal neoplasms are a heterogenous group of neoplasms arising from
      the progenitors of the cells lining the ventricular system and the spinal central
      canal.
    explanation: Identifies progenitors of ependymal lining cells as the origin of ependymal
      neoplasms.
  downstream:
  - target: ZFTA-RELA Fusion Formation
    description: Supratentorial neural stem cells transformed by ZFTA-RELA fusion give
      rise to supratentorial ependymoma.
    evidence:
    - reference: PMID:24553141
      reference_title: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: C11orf95-RELA fusion proteins translocated spontaneously to the nucleus
        to activate NF-κB target genes, and rapidly transformed neural stem cells--the
        cell of origin of ependymoma--to form these tumours in mice.
      explanation: Demonstrates in mice that the fusion transforms neural stem cells,
        the cell of origin, into ependymoma.
  - target: EZHIP Overexpression
    description: Hindbrain progenitors give rise to PFA ependymoma, which is defined by
      ectopic EZHIP overexpression.
    evidence:
    - reference: PMID:30923826
      reference_title: EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as
        an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Recently, we reported overexpression of chromosome X open reading frame
        67 (CXorf67) as a hallmark of PFA ependymoma
      explanation: Establishes EZHIP overexpression as the hallmark lesion of the posterior
        fossa group A tumors arising from this progenitor compartment.
  - target: CpG Island Methylator Phenotype Silencing
    description: Hindbrain progenitors in poor-prognosis PFA tumors acquire a CpG island
      methylator phenotype.
    evidence:
    - reference: PMID:24553142
      reference_title: Epigenomic alterations define lethal CIMP-positive ependymomas
        of infancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Ependymomas are common childhood brain tumours that occur throughout the
        nervous system, but are most common in the paediatric hindbrain.
      explanation: Locates the CIMP-positive tumors studied in this paper to the paediatric
        hindbrain progenitor compartment.
  - target: Impaired Lineage Differentiation
    description: Transformed progenitors fail to complete neuronal-glial differentiation,
      establishing a tumor cellular hierarchy.
    evidence:
    - reference: PMID:32663469
      reference_title: Single-Cell RNA-Seq Reveals Cellular Hierarchies and Impaired Developmental
        Trajectories in Pediatric Ependymoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Ependymomas are composed of a cellular hierarchy initiating from undifferentiated
        populations, which undergo impaired differentiation toward three lineages of neuronal-glial
        fate specification.
      explanation: Directly demonstrates that the transformed progenitor compartment gives
        rise to a differentiation-blocked cellular hierarchy.
- name: Impaired Lineage Differentiation
  description: >-
    Single-cell RNA sequencing shows that ependymomas are organized as a cellular
    hierarchy initiating from undifferentiated populations that undergo impaired
    differentiation toward three neuronal-glial lineages. The proportion of
    undifferentiated cells tracks with aggressiveness: favorable molecular groups
    are dominated by differentiated cells, whereas aggressive groups are enriched
    for undifferentiated populations.
  biological_processes:
  - preferred_term: cell differentiation
    modifier: DECREASED
    term:
      id: GO:0030154
      label: cell differentiation
  cell_types:
  - preferred_term: neural stem cell
    term:
      id: CL:0000047
      label: neural stem cell
  evidence:
  - reference: PMID:32663469
    reference_title: Single-Cell RNA-Seq Reveals Cellular Hierarchies and Impaired Developmental
      Trajectories in Pediatric Ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ependymomas are composed of a cellular hierarchy initiating from undifferentiated
      populations, which undergo impaired differentiation toward three lineages of neuronal-glial
      fate specification.
    explanation: Establishes the differentiation-blocked cellular hierarchy underlying
      ependymoma.
  - reference: PMID:32663469
    reference_title: Single-Cell RNA-Seq Reveals Cellular Hierarchies and Impaired Developmental
      Trajectories in Pediatric Ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: While prognostically favorable groups of ependymoma predominantly harbor
      differentiated cells, aggressive groups are enriched for undifferentiated cell
      populations.
    explanation: Links the degree of differentiation block to prognosis across molecular
      groups.
  downstream:
  - target: Uncontrolled Tumor Cell Proliferation
    description: Retention of undifferentiated progenitor populations sustains tumor
      growth.
    evidence:
    - reference: PMID:32663469
      reference_title: Single-Cell RNA-Seq Reveals Cellular Hierarchies and Impaired Developmental
        Trajectories in Pediatric Ependymoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: While prognostically favorable groups of ependymoma predominantly harbor
        differentiated cells, aggressive groups are enriched for undifferentiated cell
        populations.
      explanation: Links retained undifferentiated populations to the aggressive, proliferative
        molecular groups.
- name: ZFTA-RELA Fusion Formation
  description: >-
    The majority of supratentorial ependymomas harbor oncogenic fusions between
    RELA, the principal effector of canonical NF-kB signalling, and ZFTA
    (formerly C11orf95). These fusions arise by chromothripsis of chromosome
    11q13.1 — a single catastrophic chromosomal shattering and reassembly event
    rather than stepwise mutation. This explains how a tumor with an otherwise
    very low mutation burden acquires a potent driver.
  biological_processes:
  - preferred_term: chromatin organization
    modifier: ABNORMAL
    term:
      id: GO:0006325
      label: chromatin organization
  locations:
  - preferred_term: lateral ventricle
    term:
      id: UBERON:0002285
      label: telencephalic ventricle
  evidence:
  - reference: PMID:24553141
    reference_title: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Here we show that more than two-thirds of supratentorial ependymomas contain
      oncogenic fusions between RELA, the principal effector of canonical NF-κB signalling,
      and an uncharacterized gene, C11orf95. In each case, C11orf95-RELA fusions resulted
      from chromothripsis involving chromosome 11q13.1.'
    explanation: Establishes the frequency of the fusion in supratentorial ependymoma
      and chromothripsis as its mechanism of formation.
  - reference: PMID:29949764
    reference_title: A De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma
      Identifies Driver Functions in Addition to NF-κB.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The majority of supratentorial ependymomas (ST-ependymomas) have few mutations
      but frequently display chromothripsis of chromosome 11q that generates a fusion
      between C11orf95 and RELA
    explanation: Independently confirms the low mutation burden and chromothripsis-generated
      fusion in supratentorial ependymoma.
  downstream:
  - target: Constitutive NF-kB Pathway Activation
    description: The fusion protein translocates to the nucleus and activates NF-kB
      target genes.
    evidence:
    - reference: PMID:24553141
      reference_title: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: C11orf95-RELA fusion proteins translocated spontaneously to the nucleus
        to activate NF-κB target genes, and rapidly transformed neural stem cells--the
        cell of origin of ependymoma--to form these tumours in mice.
      explanation: Shows the fusion protein drives NF-kB target gene activation. Graded
        MODEL_ORGANISM because the sentence reports tumour formation in mice; the same
        sentence carries both the nuclear-translocation and the in vivo transformation
        result, so it is not split.
- name: Constitutive NF-kB Pathway Activation
  conforms_to: sustaining_proliferative_signaling#Constitutive Mitogenic Pathway Activation
  description: >-
    ZFTA-RELA fusion proteins localize spontaneously to the nucleus and
    constitutively activate canonical NF-kB target gene transcription,
    independently of upstream inflammatory signalling. This is a rare example of
    a recurrent genetic lesion directly activating NF-kB in human cancer, since
    constitutive NF-kB signalling is common in tumors but pathway mutations are
    otherwise rare. Mouse modelling indicates that additional driver functions
    beyond NF-kB contribute to tumorigenesis.
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    modifier: INCREASED
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
  - preferred_term: regulation of DNA-templated transcription
    modifier: DYSREGULATED
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
  evidence:
  - reference: PMID:24553141
    reference_title: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Although constitutive NF-κB signalling is present in most human tumours,
      mutations in pathway members are rare, complicating efforts to understand and
      block aberrant NF-κB activity in cancer.
    explanation: Frames the ZFTA-RELA fusion as an unusual recurrent genetic activator
      of NF-kB, motivating its role as a driver lesion.
  downstream:
  - target: Uncontrolled Tumor Cell Proliferation
    description: NF-kB target gene programs drive proliferation and survival of transformed
      progenitors.
    evidence:
    - reference: PMID:29949764
      reference_title: A De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma
        Identifies Driver Functions in Addition to NF-κB.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: These tumors display enhanced NF-κB signaling, suggesting that this aberrant
        signal is the principal mechanism of oncogenesis.
      explanation: Supports NF-kB signalling as the principal oncogenic output of the fusion,
        while the same study shows additional driver functions contribute.
- name: EZHIP Overexpression
  conforms_to: epigenetic_alterations#Altered Epigenetic Regulation of Gene Expression
  description: >-
    Posterior fossa type A ependymomas overexpress EZHIP (also called CXorf67).
    Overexpression, not mutation, is the lesion: EZHIP is a normally
    germline-restricted protein whose ectopic expression in hindbrain progenitors
    is the hallmark of the PFA methylation class.
  locations:
  - preferred_term: fourth ventricle
    term:
      id: UBERON:0002422
      label: fourth ventricle
  evidence:
  - reference: PMID:30923826
    reference_title: EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as
      an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Recently, we reported overexpression of chromosome X open reading frame
      67 (CXorf67) as a hallmark of PFA ependymoma
    explanation: Establishes EZHIP/CXorf67 overexpression as the hallmark lesion of PFA
      ependymoma, reported in human PFA tumor cohorts.
  downstream:
  - target: PRC2 Catalytic Inhibition
    description: EZHIP protein binds and inhibits the PRC2 catalytic subunit EZH2.
    evidence:
    - reference: PMID:30923826
      reference_title: EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as
        an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: showed that CXorf67 can interact with enhancer of zeste homolog 2 (EZH2),
        thereby inhibiting polycomb repressive complex 2 (PRC2)
      explanation: Links EZHIP overexpression to direct inhibition of PRC2 through EZH2.
- name: PRC2 Catalytic Inhibition
  conforms_to: epigenetic_alterations#Altered Epigenetic Regulation of Gene Expression
  description: >-
    A short, highly conserved C-terminal peptide of EZHIP mimics the sequence of
    K27M-mutated histones and contacts the active site of the EZH2 subunit,
    blocking PRC2 methyltransferase activity. EZHIP therefore acts as an
    "oncohistone mimic", producing the same functional lesion as the H3 K27M
    mutation of diffuse midline glioma without any histone mutation.
  biological_processes:
  - preferred_term: facultative heterochromatin formation
    modifier: DECREASED
    term:
      id: GO:0140718
      label: facultative heterochromatin formation
  evidence:
  - reference: PMID:31086175
    reference_title: PFA ependymoma-associated protein EZHIP inhibits PRC2 activity
      through a H3 K27M-like mechanism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here we find that a conserved sequence in EZHIP is necessary and sufficient
      to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts
      the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone.
    explanation: Establishes the biochemical mechanism by which EZHIP inhibits PRC2 catalysis.
  downstream:
  - target: Global H3K27me3 Loss
    description: Loss of PRC2 catalytic activity prevents deposition and spreading of
      the H3K27me3 mark.
    evidence:
    - reference: PMID:31086175
      reference_title: PFA ependymoma-associated protein EZHIP inhibits PRC2 activity
        through a H3 K27M-like mechanism.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'Furthermore, expression of H3 K27M or EZHIP in cells promotes similar
        chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3
        at CpG islands.'
      explanation: Links PRC2 inhibition directly to the loss of broad H3K27me3 domains.
- name: Global H3K27me3 Loss
  conforms_to: epigenetic_alterations#Altered Epigenetic Regulation of Gene Expression
  description: >-
    PFA ependymomas are characterized by global depletion of the repressive
    H3K27me3 mark, with loss of broad domains but retention at CpG islands. The
    resulting de-repression of PRC2 target genes is the defining epigenetic
    lesion of the group and is used diagnostically as an immunohistochemical
    surrogate.
  biological_processes:
  - preferred_term: negative regulation of gene expression, epigenetic
    modifier: DECREASED
    term:
      id: GO:0045814
      label: negative regulation of gene expression, epigenetic
  evidence:
  - reference: PMID:30923826
    reference_title: EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as
      an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: PFA tumors are mainly diagnosed in infants and young children, show a poor
      prognosis, and are characterized by a lack of the repressive histone H3 lysine
      27 trimethylation (H3K27me3) mark.
    explanation: Documents global H3K27me3 loss as the defining feature of PFA tumors.
  downstream:
  - target: Impaired Lineage Differentiation
    description: De-repression of PRC2 target neurodevelopmental genes prevents orderly
      lineage maturation.
    evidence:
    - reference: PMID:30923826
      reference_title: EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as
        an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: causing de-repression of PRC2 target genes, including genes involved in
        neurodevelopment
      explanation: Links loss of PRC2-mediated repression directly to de-repression of
        neurodevelopmental genes, the basis of the differentiation block.
- name: CpG Island Methylator Phenotype Silencing
  conforms_to: epigenetic_alterations#Altered Epigenetic Regulation of Gene Expression
  description: >-
    Poor-prognosis hindbrain ependymomas independently exhibit a CpG island
    methylator phenotype (CIMP). Transcriptional silencing driven by CpG
    methylation converges on the same Polycomb repressive complex 2 targets,
    reinforcing the differentiation block. This epigenetic program, rather than
    recurrent point mutation, drives tumorigenesis — these tumors have an
    extremely low mutation rate with no significant recurrent somatic single
    nucleotide variants.
  biological_processes:
  - preferred_term: negative regulation of gene expression, epigenetic
    modifier: DYSREGULATED
    term:
      id: GO:0045814
      label: negative regulation of gene expression, epigenetic
  evidence:
  - reference: PMID:24553142
    reference_title: Epigenomic alterations define lethal CIMP-positive ependymomas
      of infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Transcriptional silencing driven by CpG methylation converges exclusively
      on targets of the Polycomb repressive complex 2 which represses expression of
      differentiation genes through trimethylation of H3K27.
    explanation: Establishes convergence of CIMP-driven silencing on PRC2 targets in
      poor-prognosis hindbrain ependymoma.
  - reference: PMID:24553142
    reference_title: Epigenomic alterations define lethal CIMP-positive ependymomas
      of infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Whole-genome and whole-exome sequencing of 47 hindbrain ependymomas reveals
      an extremely low mutation rate, and zero significant recurrent somatic single
      nucleotide variants.
    explanation: Documents the very low mutational burden, supporting an epigenetic rather
      than mutational driver mechanism.
  downstream:
  - target: Impaired Lineage Differentiation
    description: De-repression and dysregulation of PRC2 target differentiation genes
      blocks normal lineage maturation.
    evidence:
    - reference: PMID:24553142
      reference_title: Epigenomic alterations define lethal CIMP-positive ependymomas
        of infancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Transcriptional silencing driven by CpG methylation converges exclusively
        on targets of the Polycomb repressive complex 2 which represses expression of
        differentiation genes through trimethylation of H3K27.
      explanation: Shows the silencing converges on PRC2-repressed differentiation genes,
        the mechanistic basis of the differentiation block.
  - target: Uncontrolled Tumor Cell Proliferation
    description: Failure to silence differentiation programs maintains progenitors in
      a proliferative state.
    evidence:
    - reference: PMID:24553142
      reference_title: Epigenomic alterations define lethal CIMP-positive ependymomas
        of infancy.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CpG island methylator phenotype-positive hindbrain ependymomas are responsive
        to clinical drugs that target either DNA or H3K27 methylation both in vitro and
        in vivo.
      explanation: Pharmacological reversal of the methylation lesion restrains these tumors,
        showing the epigenetic block is what sustains their growth.
- name: NF2 Loss in Spinal Ependymoma
  conforms_to: evading_growth_suppressors#Tumor Suppressor Inactivation
  description: >-
    Classic spinal ependymoma is characterized by biallelic inactivation of the
    NF2 tumor suppressor on chromosome 22q, arising from a germline or somatic
    NF2 mutation combined with loss of chromosome 22q. NF2 encodes merlin, a
    membrane-cytoskeleton scaffold that restrains growth signalling; its loss is
    the only recurrent genetic event in this methylation class.
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  evidence:
  - reference: PMID:38265489
    reference_title: Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN)
      identifies clinically relevant subtypes enriched for tumors with and without NF2
      mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The only known recurrent genetic events in SP-EPN are loss of chromosome
      22q and NF2 mutations
    explanation: Establishes 22q loss and NF2 mutation as the recurrent genetic events in
      spinal ependymoma.
  downstream:
  - target: Uncontrolled Tumor Cell Proliferation
    description: Loss of merlin-mediated growth suppression permits progenitor expansion.
    evidence:
    - reference: PMID:38265489
      reference_title: Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN)
        identifies clinically relevant subtypes enriched for tumors with and without NF2
        mutation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The only known recurrent genetic events in SP-EPN are loss of chromosome
        22q and NF2 mutations
      explanation: Identifies NF2 loss as the sole recurrent driver lesion in this compartment,
        implicating it in tumor cell outgrowth.
- name: MYCN Amplification in Spinal Ependymoma
  conforms_to: sustaining_proliferative_signaling#Oncogenic Growth-Signal Lesion
  description: >-
    A rare spinal ependymal tumor subgroup identified by DNA methylation
    profiling carries MYCN amplification in all reported cases. MYCN
    amplification drives an aggressive phenotype with spinal cord infiltration
    and CNS dissemination, in contrast to the generally good prognosis of other
    spinal ependymal tumors.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
  evidence:
  - reference: PMID:31414211
    reference_title: MYCN amplification drives an aggressive form of spinal ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe a new and relatively rare subgroup of spinal ependymal
      tumors identified using DNA methylation profiling that is distinct from other
      molecular subgroups of ependymoma.
    explanation: Establishes MYCN-amplified spinal ependymoma as a distinct methylation-defined
      subgroup.
  downstream:
  - target: CNS Dissemination
    description: MYCN-amplified spinal tumors infiltrate the spinal cord and disseminate
      through the CNS.
    evidence:
    - reference: PMID:31414211
      reference_title: MYCN amplification drives an aggressive form of spinal ependymoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: However, their treatment can be challenging if infiltration of the spinal
        cord or dissemination throughout the central nervous system (CNS) occurs and,
        in these cases, clinical outcome remains poor.
      explanation: Links spinal cord infiltration and CNS dissemination to poor clinical
        outcome.
- name: Uncontrolled Tumor Cell Proliferation
  conforms_to: evading_growth_suppressors#Unrestrained Proliferation
  description: >-
    Convergent consequence of the compartment-specific driver lesions. Whether
    initiated by fusion-driven NF-kB transcription, PRC2 inhibition, NF2 loss, or
    MYCN amplification, transformed ependymal progenitors proliferate without
    normal growth restraint and form an expanding intraventricular or
    intramedullary mass.
  biological_processes:
  - preferred_term: cell population proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  cell_types:
  - preferred_term: ependymal cell
    term:
      id: CL:0000065
      label: ependymal cell
  evidence:
  - reference: PMID:32663469
    reference_title: Single-Cell RNA-Seq Reveals Cellular Hierarchies and Impaired Developmental
      Trajectories in Pediatric Ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: aggressive groups are enriched for undifferentiated cell populations
    explanation: Associates the proliferative, undifferentiated cell compartment with the
      aggressive molecular groups, supporting unrestrained proliferation as the convergent
      outcome.
  downstream:
  - target: Cerebrospinal Fluid Pathway Obstruction
    description: An enlarging posterior fossa or intraventricular mass obstructs CSF
      flow.
    evidence:
    - reference: PMID:40556668
      reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
        review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Clinical symptoms vary by location, with posterior fossa tumors often causing
        hydrocephalus-related signs
      explanation: Links posterior fossa tumor growth to obstructive hydrocephalus.
  - target: CNS Dissemination
    description: Tumor cells seed the leptomeninges via the cerebrospinal fluid.
    evidence:
    - reference: PMID:40556668
      reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
        review.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: with dissemination present in up to 10% of cases at diagnosis
      explanation: Quantifies leptomeningeal dissemination arising from the primary tumor.
- name: Cerebrospinal Fluid Pathway Obstruction
  description: >-
    Posterior fossa ependymomas characteristically arise in or extend into the
    fourth ventricle, where they obstruct cerebrospinal fluid pathways. The
    resulting non-communicating hydrocephalus and raised intracranial pressure
    produce the classic presenting syndrome of headache, vomiting and
    papilledema.
  locations:
  - preferred_term: fourth ventricle
    term:
      id: UBERON:0002422
      label: fourth ventricle
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical symptoms vary by location, with posterior fossa tumors often causing
      hydrocephalus-related signs, and supratentorial lesions presenting with seizures
      or focal deficits.
    explanation: Links posterior fossa location to hydrocephalus and supratentorial location
      to seizures and focal deficits.
  downstream:
  - target: Raised Intracranial Pressure Syndrome
    description: Obstructed CSF outflow raises intracranial pressure.
    evidence:
    - reference: PMID:8677342
      reference_title: 'Intracranial supratentorial tumors: classification, clinical findings,
        surgical management.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: A tumor hindering CSF circulation may cause hydrocephalus.
      explanation: States the causal link from obstructed CSF circulation to hydrocephalus
        and raised intracranial pressure.
- name: Raised Intracranial Pressure Syndrome
  description: >-
    Clinical endpoint of CSF obstruction: progressive hydrocephalus with
    headache, vomiting, papilledema and, in infants, macrocephaly and a bulging
    fontanelle. This is the dominant presenting syndrome for posterior fossa
    ependymoma and the reason urgent surgical decompression is frequently
    required.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:8677342
    reference_title: 'Intracranial supratentorial tumors: classification, clinical findings,
      surgical management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Signs and symptoms related to increased intracranial pressure are often reported
      and vary according to the patient's age.
    explanation: Establishes the raised intracranial pressure syndrome and its age-dependent
      presentation in paediatric intracranial tumors.
- name: CNS Dissemination
  conforms_to: invasion_and_metastasis#Local Invasion and Intravasation
  description: >-
    Ependymoma spreads through the cerebrospinal fluid rather than
    haematogenously. Leptomeningeal dissemination is present at diagnosis in up
    to 10% of intracranial cases, which is why staging includes craniospinal
    imaging and CSF cytology, and why craniospinal irradiation is reserved for
    documented metastatic disease.
  locations:
  - preferred_term: ventricular system of brain
    term:
      id: UBERON:0005282
      label: ventricular system of brain
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diagnosis requires histologic confirmation, aided by MRI and cerebrospinal
      fluid analysis, with dissemination present in up to 10% of cases at diagnosis.
    explanation: Quantifies the frequency of dissemination at diagnosis and the role of
      CSF analysis in staging.
histopathology:
- name: Perivascular Pseudorosettes
  finding_term:
    preferred_term: Perivascular pseudorosette formation
    term:
      id: NCIT:C41626
      label: Perivascular Pseudorosette Formation
  description: >-
    Tumor cells arranged radially around blood vessels with a perivascular
    anucleate fibrillary zone. This is the most consistent diagnostic
    histological feature of ependymoma across compartments and molecular groups,
    and is accompanied by GFAP and EMA positivity.
  evidence:
  - reference: PMID:31414211
    reference_title: MYCN amplification drives an aggressive form of spinal ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Histological re-evaluation in five primary tumors and seven relapses showed
      characteristic histological features of ependymoma, namely pseudorosettes, GFAP-
      and EMA positivity.
    explanation: Identifies pseudorosettes together with GFAP and EMA positivity as the
      characteristic histological features of ependymoma.
- name: Ependymal Rosettes
  finding_term:
    preferred_term: Ependymal rosette formation
    term:
      id: NCIT:C35944
      label: Ependymal Rosette Formation
  description: >-
    True ependymal rosettes — tumor cells arranged around a central lumen
    recapitulating the ependymal canal — are highly specific for ependymoma but
    much less frequent than perivascular pseudorosettes.
  evidence:
  - reference: PMID:11211057
    reference_title: Brain surface ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: forming true ependymal rosettes and perivascular pseudorosettes with fibrillary
      background
    explanation: Describes true ependymal rosettes occurring alongside perivascular pseudorosettes
      in a histologically confirmed ependymoma.
phenotypes:
- category: Neurologic
  name: Hydrocephalus
  description: >-
    Obstruction of cerebrospinal fluid pathways by a fourth-ventricular or
    intraventricular mass produces non-communicating hydrocephalus. This is the
    dominant presenting feature of posterior fossa ependymoma.
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical symptoms vary by location, with posterior fossa tumors often causing
      hydrocephalus-related signs, and supratentorial lesions presenting with seizures
      or focal deficits.
    explanation: Directly associates posterior fossa ependymoma with hydrocephalus-related
      clinical signs.
- category: Neurologic
  name: Headache
  description: >-
    Headache from raised intracranial pressure, characteristically worse in the
    morning and progressive, accompanying obstructive hydrocephalus. Present in
    older children rather than infants, who instead show macrocrania.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
    temporality: PROLONGED
  evidence:
  - reference: PMID:8677342
    reference_title: 'Intracranial supratentorial tumors: classification, clinical findings,
      surgical management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Macrocrania and a bulging fontanel can be observed in infants and toddlers,
      whereas headache, papilledema and vomiting are present in the older children.
    explanation: Documents the age-dependent signs of raised intracranial pressure in
      paediatric intracranial tumors, the mechanism by which this feature arises in ependymoma.
- category: Gastrointestinal
  name: Vomiting
  description: >-
    Vomiting secondary to raised intracranial pressure, often without nausea and
    typically worse on waking.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: nausea, vomiting, ataxia, vertigo, and papilledema
    explanation: Ependymoma-specific source listing this sign among the presenting features
      of posterior fossa ependymoma with obstructive hydrocephalus.
  - reference: PMID:8677342
    reference_title: 'Intracranial supratentorial tumors: classification, clinical findings,
      surgical management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Macrocrania and a bulging fontanel can be observed in infants and toddlers,
      whereas headache, papilledema and vomiting are present in the older children.
    explanation: Documents the age-dependent signs of raised intracranial pressure in
      paediatric intracranial tumors, the mechanism by which this feature arises in ependymoma.
- category: Ophthalmologic
  name: Papilledema
  description: >-
    Optic disc swelling from transmitted raised intracranial pressure, a physical
    sign of obstructive hydrocephalus seen in older children.
  phenotype_term:
    preferred_term: Papilledema
    term:
      id: HP:0001085
      label: Papilledema
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: nausea, vomiting, ataxia, vertigo, and papilledema
    explanation: Ependymoma-specific source listing this sign among the presenting features
      of posterior fossa ependymoma with obstructive hydrocephalus.
  - reference: PMID:8677342
    reference_title: 'Intracranial supratentorial tumors: classification, clinical findings,
      surgical management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Macrocrania and a bulging fontanel can be observed in infants and toddlers,
      whereas headache, papilledema and vomiting are present in the older children.
    explanation: Documents the age-dependent signs of raised intracranial pressure in
      paediatric intracranial tumors, the mechanism by which this feature arises in ependymoma.
- category: Neurologic
  name: Seizure
  description: >-
    Seizures are a characteristic presenting feature of supratentorial
    ependymoma, reflecting cortical rather than posterior fossa involvement.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical symptoms vary by location, with posterior fossa tumors often causing
      hydrocephalus-related signs, and supratentorial lesions presenting with seizures
      or focal deficits.
    explanation: Associates supratentorial ependymoma specifically with seizures.
- category: Neurologic
  name: Ataxia
  description: >-
    Truncal and appendicular ataxia from cerebellar compression by a posterior
    fossa mass.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: nausea, vomiting, ataxia, vertigo, and papilledema
    explanation: Lists ataxia among the presenting features of posterior fossa ependymoma
      with obstructive hydrocephalus.
- category: Craniofacial
  name: Macrocephaly
  description: >-
    Progressive head enlargement in infants and toddlers whose open sutures
    accommodate rising intracranial pressure, in place of the headache and
    papilledema seen in older children.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:8677342
    reference_title: 'Intracranial supratentorial tumors: classification, clinical findings,
      surgical management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Macrocrania and a bulging fontanel can be observed in infants and toddlers,
      whereas headache, papilledema and vomiting are present in the older children.
    explanation: Documents the age-dependent signs of raised intracranial pressure in
      paediatric intracranial tumors, the mechanism by which this feature arises in ependymoma.
- category: Neurologic
  name: Back Pain
  description: >-
    Back pain is a common presenting symptom of spinal ependymoma; clinical onset
    depends largely on the spinal level involved and may include both
    non-specific and localizing sensory or motor symptoms.
  phenotype_term:
    preferred_term: Back pain
    term:
      id: HP:0003418
      label: Back pain
  frequency: FREQUENT
  evidence:
  - reference: PMID:38074692
    reference_title: 'Spinal ependymoma in adults: from molecular advances to new treatment
      perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: are the most common (58%), followed by weakness (45%), back pain (35%),
      and radiating back pain (27%)
    explanation: Gives the frequency of back pain (35%) among presenting symptoms of adult
      spinal ependymoma, supporting both the association and the FREQUENT band.
- category: Neurologic
  name: Dysesthesia
  description: >-
    Sensory symptoms, particularly dysesthesias (numbness and tingling), are the
    most common presenting complaint of adult spinal ependymoma, typically
    beginning distally in the lower limbs with proximal progression.
  phenotype_term:
    preferred_term: Dysesthesia
    term:
      id: HP:0012534
      label: Dysesthesia
  frequency: FREQUENT
  evidence:
  - reference: PMID:38074692
    reference_title: 'Spinal ependymoma in adults: from molecular advances to new treatment
      perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: are the most common (58%), followed by weakness (45%)
    explanation: Gives the frequency of dysesthesia (58%, the most common presenting
      symptom) in adult spinal ependymoma, supporting both the association and the
      FREQUENT band.
- category: Neurologic
  name: Muscle Weakness
  description: >-
    Limb weakness affects roughly 45% of adults with spinal ependymoma and
    indicates that the tumor has significantly thinned the surrounding spinal
    cord.
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  frequency: FREQUENT
  evidence:
  - reference: PMID:38074692
    reference_title: 'Spinal ependymoma in adults: from molecular advances to new treatment
      perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: are the most common (58%), followed by weakness (45%), back pain (35%), and
      radiating back pain (27%)
    explanation: Gives the frequency of weakness (45%) among presenting symptoms of adult
      spinal ependymoma, supporting both the association and the FREQUENT band.
- category: Genitourinary
  name: Urinary Sphincter Dysfunction
  description: >-
    Urinary sphincter dysfunction with incontinence occurs in spinal ependymoma,
    particularly with conus medullaris and cauda equina involvement, and is a
    common symptom of anaplastic spinal disease.
  phenotype_term:
    preferred_term: urinary incontinence
    term:
      id: HP:0000020
      label: Urinary incontinence
  evidence:
  - reference: PMID:38074692
    reference_title: 'Spinal ependymoma in adults: from molecular advances to new treatment
      perspectives.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: limb weakness, and sphincter dysfunction
    explanation: Lists sphincter dysfunction among the common symptoms of anaplastic spinal
      ependymoma.
- category: Neurologic
  name: Cranial Nerve Palsy
  description: >-
    Cranial nerve palsies, particularly of nerves VI to X, are frequent with
    posterior fossa ependymoma; laterally located tumors extending through the
    foramina of Luschka may cause dysphagia and dysarthria.
  phenotype_term:
    preferred_term: cranial nerve palsy
    term:
      id: HP:0031910
      label: Abnormal cranial nerve physiology
  frequency: FREQUENT
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cranial nerve palsies — particularly of nerves VI to X — are frequent
    explanation: Establishes cranial nerve palsy as a frequent feature of posterior fossa
      ependymoma.
genetic:
- name: ZFTA
  association: Fusion
  notes: >-
    ZFTA (formerly C11orf95) fusion, most commonly ZFTA-RELA, defines the
    dominant supratentorial ependymoma type and is present in more than
    two-thirds of supratentorial cases. Fusions arise by chromothripsis of
    11q13.1. Non-RELA ZFTA fusion partners (including NCOA1/2) produce the same
    histomolecular entity but with marked histopathological heterogeneity.
  evidence:
  - reference: PMID:34389065
    reference_title: 'Supratentorial non-RELA, ZFTA-fused ependymomas: a comprehensive
      phenotype genotype correlation highlighting the number of zinc fingers in ZFTA-NCOA1/2
      fusions.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This modification reinforces the idea that supratentorial-ependymomas exhibiting
      fusion that implicates the C11orf95 (now called ZFTA) gene with or without the
      RELA gene, represent the same histomolecular entity.
    explanation: Confirms ZFTA fusions with or without RELA define a single histomolecular
      entity.
- name: RELA
  association: Fusion
  notes: >-
    RELA, the principal effector of canonical NF-kB signalling, is the most
    frequent ZFTA fusion partner. The resulting fusion protein enters the nucleus
    spontaneously and constitutively activates NF-kB target genes.
  evidence:
  - reference: PMID:24553141
    reference_title: C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our data identify a highly recurrent genetic alteration of RELA in human
      cancer
    explanation: Establishes RELA fusion as a highly recurrent genetic alteration in this
      tumor.
- name: YAP1
  association: Fusion
  notes: >-
    YAP1 fusion defines the second, less common supratentorial ependymoma type,
    recognized as a distinct subtype in WHO CNS5. YAP1-fused tumors generally
    affect younger children and carry a better prognosis than ZFTA-fused tumors.
  evidence:
  - reference: PMID:25965575
    reference_title: Molecular Classification of Ependymal Tumors across All CNS Compartments,
      Histopathological Grades, and Age Groups.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two supratentorial subgroups are characterized by prototypic fusion genes
      involving RELA and YAP1, respectively.
    explanation: Identifies YAP1 fusion as defining a distinct supratentorial molecular
      subgroup.
- name: EZHIP
  association: Overexpression
  notes: >-
    EZHIP (also known as CXORF67) is highly expressed in PFA ependymoma and acts
    as a peptidyl PRC2 inhibitor, an "oncohistone mimic" functionally analogous
    to the H3 K27M mutation of diffuse midline glioma. EZHIP overexpression, not
    mutation, is the driver.
  evidence:
  - reference: PMID:31086175
    reference_title: PFA ependymoma-associated protein EZHIP inhibits PRC2 activity
      through a H3 K27M-like mechanism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation
      and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein,
      also termed CXORF67).
    explanation: Documents EZHIP overexpression and low H3K27 methylation as features
      of PFA ependymoma.
- name: NF2
  association: Loss of Function
  notes: >-
    Biallelic NF2 inactivation (22q12), through germline or somatic mutation
    combined with chromosome 22q loss, is the recurrent genetic event in classic
    spinal ependymoma. Germline NF2 mutation causes NF2-related schwannomatosis,
    the principal hereditary predisposition to ependymoma.
  evidence:
  - reference: PMID:38265489
    reference_title: Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN)
      identifies clinically relevant subtypes enriched for tumors with and without NF2
      mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The only known recurrent genetic events in SP-EPN are loss of chromosome
      22q and NF2 mutations
    explanation: Establishes NF2 mutation and 22q loss as the recurrent genetic events in
      spinal ependymoma.
- name: MYCN
  association: Amplification
  notes: >-
    MYCN amplification defines the aggressive spinal ependymoma type added in WHO
    CNS5, and was present in all cases of the original defining cohort. Tumors
    were histologically anaplastic (WHO grade III) in ten of thirteen cases.
  evidence:
  - reference: PMID:31414211
    reference_title: MYCN amplification drives an aggressive form of spinal ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The histological diagnosis was anaplastic ependymoma (WHO Grade III) in
      ten cases and classic ependymoma (WHO Grade II) in three cases.
    explanation: Documents the histological grade distribution of MYCN-amplified spinal
      ependymoma.
- name: Chromosome 1q
  association: Gain
  notes: >-
    Gain of chromosome 1q is the best-established adverse copy-number biomarker in
    intracranial ependymoma, correlating with pediatric age and functioning as an
    independent prognostic marker. It was evaluated prospectively as a
    stratification variable in the COG ACNS0121 trial.
  evidence:
  - reference: PMID:16609018
    reference_title: Identification of gains on 1q and epidermal growth factor receptor
      overexpression as independent prognostic markers in intracranial ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: gain of 1q25 as determined by fluorescence in situ hybridization represented
      an independent prognostic marker
    explanation: Establishes 1q25 gain as an independent prognostic marker in intracranial
      ependymoma, supporting the adverse-biomarker claim.
- name: CDKN2A
  association: Homozygous Deletion
  notes: >-
    Homozygous deletion of CDKN2A/CDKN2B is an adverse copy-number marker in
    intracranial ependymoma, used together with 1q gain and age at diagnosis in
    molecular staging schemes that complement histopathological classification.
  evidence:
  - reference: PMID:20516456
    reference_title: Molecular staging of intracranial ependymoma in children and adults.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised
      the most powerful independent indicators of unfavorable prognosis
    explanation: Directly identifies homozygous CDKN2A deletion as one of the most powerful
      independent adverse prognostic indicators in intracranial ependymoma.
- name: EGFR
  association: Overexpression
  notes: >-
    EGFR at 7p11.2 shows frequent gains and high-level amplification in
    intracranial ependymoma, and protein overexpression by immunohistochemistry
    is an independent adverse prognostic marker that stratifies grade 2 tumors
    into distinct risk groups.
  evidence:
  - reference: PMID:16609018
    reference_title: Identification of gains on 1q and epidermal growth factor receptor
      overexpression as independent prognostic markers in intracranial ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: EGFR protein status subdivides intracranial grade II ependymomas into two
      different risk groups
    explanation: Establishes EGFR protein overexpression as a prognostic stratifier in
      intracranial ependymoma.
environmental:
- name: High-dose ionizing radiation
  description: >-
    High-dose ionizing radiation is the only established environmental risk factor
    for childhood CNS tumors including ependymoma. Investigations of other
    environmental aetiologies, including dietary N-nitroso compounds, have not
    produced consistent associations, and ependymoma is otherwise largely
    sporadic.
  presence: PRESENT
  evidence:
  - reference: PMID:16142778
    reference_title: 'Central nervous system tumours in children: epidemiology and risk
      factors.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Whilst high dose ionising radiation is an established risk factor for this
      group of tumours, reported associations with dietary N-nitroso compounds have
      not been consistent
    explanation: Establishes high-dose ionizing radiation as the only confirmed environmental
      risk factor for childhood CNS tumors.
inheritance:
- name: Autosomal Dominant
  description: >-
    Most ependymomas are sporadic. The principal hereditary predisposition is
    NF2-related schwannomatosis (formerly neurofibromatosis type 2), an autosomal
    dominant tumor-predisposition syndrome caused by germline NF2 mutation on
    chromosome 22, in which spinal ependymomas are a common tumor. Fifty to sixty
    percent of patients represent de novo mutations and up to a third of those are
    mosaic, which complicates genetic testing and counseling.
  inheritance_term:
    preferred_term: autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:23931824
    reference_title: 'Neurofibromatosis type 2 (NF2): diagnosis and management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neurofibromatosis type 2 (NF2) is an autosomal dominant inherited tumor
      predisposition syndrome caused by mutations in the NF2 gene on chromosome 22.
    explanation: Establishes the autosomal dominant inheritance and genetic basis of the
      predisposition syndrome.
  - reference: PMID:23931824
    reference_title: 'Neurofibromatosis type 2 (NF2): diagnosis and management.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cranial and spinal meningiomas and spinal ependymomas are other common tumors.
    explanation: Documents spinal ependymoma as a common tumor in NF2-related schwannomatosis.
animal_models:
- species: Mouse (Mus musculus)
  genotype: C11orf95-RELA (ZFTA-RELA) fusion expressed in periventricular neural stem
    cells
  category: Transgenic
  description: >-
    De novo mouse model in which the C11orf95-RELA fusion is introduced into
    periventricular neural stem cells, generating supratentorial ependymoma. The
    model established that the fusion is sufficient to drive tumorigenesis in vivo
    and identified driver functions beyond NF-kB signalling. Limitation: it models
    only the supratentorial ZFTA-fused compartment and does not recapitulate PFA
    biology, for which EZHIP is eutherian-specific.
  genes:
  - preferred_term: RELA
    term:
      id: hgnc:9955
      label: RELA
  associated_phenotypes:
  - Supratentorial ependymoma
  evidence:
  - reference: PMID:29949764
    reference_title: A De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma
      Identifies Driver Functions in Addition to NF-κB.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We show that RELAFUS drives ST-ependymoma formation from periventricular
      neural stem cells in mice
    explanation: Demonstrates that the fusion alone initiates supratentorial ependymoma
      from periventricular neural stem cells in vivo.
treatments:
- name: Maximal Safe Surgical Resection
  description: >-
    Complete surgical resection is the single most important prognostic and
    therapeutic intervention across all ependymoma compartments and molecular
    groups. A complete resection should be attempted whenever possible, at first
    surgery or at reoperation.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:35384591
    reference_title: 'Ependymoma: Evaluation and Management Updates.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The majority of studies have shown a major impact of extent of resection;
      thus, a complete resection must be performed, whenever possible, at first surgery
      or at reoperation.'
    explanation: Establishes extent of resection as the dominant modifiable prognostic
      factor and complete resection as the surgical goal.
- name: Conformal Radiation Therapy
  description: >-
    Focal conformal radiotherapy is recommended for grade 3 tumors and for
    incompletely resected grade 2 tumors. In the Children's Oncology Group
    ACNS0121 trial, immediate postoperative conformal radiation therapy was
    delivered to a cumulative dose of 59.4 Gy with a 1.0-cm clinical target
    volume margin.
  treatment_term:
    preferred_term: radiation therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  evidence:
  - reference: PMID:35384591
    reference_title: 'Ependymoma: Evaluation and Management Updates.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Conformal radiotherapy is recommended for grade 3 or incompletely resected
      grade II tumors.
    explanation: States the indication for conformal radiotherapy by grade and extent
      of resection.
  - reference: PMID:30811284
    reference_title: Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy
      for Incompletely Resected Ependymoma, and Observation for Completely Resected,
      Supratentorial Ependymoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CRT was administered with a 1.0-cm clinical target volume margin. The cumulative
      total dose was 59.4 Gy
    explanation: Documents the conformal radiotherapy dose and margin used in the ACNS0121
      cooperative group trial.
- name: Proton Beam Radiation Therapy
  description: >-
    Proton therapy is increasingly used, especially in children, to reduce the
    dose delivered to developing normal brain and thereby lower the risk of
    neurocognitive and endocrine late effects.
  treatment_term:
    preferred_term: proton beam radiation therapy
    term:
      id: NCIT:C66897
      label: Proton Beam Radiation Therapy
  evidence:
  - reference: PMID:35384591
    reference_title: 'Ependymoma: Evaluation and Management Updates.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Proton therapy is increasingly employed especially in children to reduce
      the risk of neurocognitive and endocrine sequelae.
    explanation: States the rationale and paediatric preference for proton therapy.
- name: Craniospinal Irradiation
  description: >-
    Craniospinal irradiation is reserved for documented metastatic
    (leptomeningeal) disease rather than being used routinely, because of its
    substantial neurocognitive and growth toxicity.
  treatment_term:
    preferred_term: craniospinal irradiation
    term:
      id: NCIT:C116437
      label: Craniospinal Irradiation
  evidence:
  - reference: PMID:35384591
    reference_title: 'Ependymoma: Evaluation and Management Updates.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Craniospinal irradiation is reserved for metastatic disease.
    explanation: Defines metastatic disease as the indication for craniospinal irradiation.
- name: Salvage Chemotherapy
  description: >-
    Cytotoxic chemotherapy has no established role as primary therapy for
    ependymoma and does not improve survival when added to surgery and radiation.
    It is used as salvage treatment for patients failing surgery and
    radiotherapy, and to delay irradiation in infants or after subtotal
    resection.
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
  evidence:
  - reference: PMID:35384591
    reference_title: 'Ependymoma: Evaluation and Management Updates.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Chemotherapy is not useful as primary treatment and is commonly employed
      as salvage treatment for patients failing surgery and radiotherapy.
    explanation: Establishes that chemotherapy is a salvage rather than primary modality.
  - reference: PMID:24553142
    reference_title: Epigenomic alterations define lethal CIMP-positive ependymomas
      of infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Current standard therapy comprises surgery and radiation, but not cytotoxic
      chemotherapy as it does not further increase survival.
    explanation: Confirms that cytotoxic chemotherapy does not add a survival benefit
      to surgery and radiation.
- name: Locoregional CAR T-Cell Therapy
  description: >-
    Experimental, not standard of care. Because PFA ependymomas and their
    recurrences sit adjacent to and are bathed by cerebrospinal fluid,
    intrathecal delivery of chimeric antigen receptor T cells against EPHA2, HER2
    and IL13Rα2 bypasses the blood-brain barrier. Validated to date only in mouse
    xenograft models.
  treatment_term:
    preferred_term: chimeric antigen receptor T-cell therapy
    term:
      id: NCIT:C126102
      label: Chimeric Antigen Receptor T-Cell Therapy
  evidence:
  - reference: PMID:32341580
    reference_title: Locoregional delivery of CAR T cells to the cerebrospinal fluid
      for treatment of metastatic medulloblastoma and ependymoma.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor
      α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic
      and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models.
    explanation: Preclinical mouse-xenograft evidence for intrathecal CAR T-cell therapy
      in PFA ependymoma; not yet clinically established.
diagnosis:
- name: DNA methylation array profiling
  description: >-
    Genome-wide DNA methylation profiling is the reference method for assigning
    an ependymal tumor to its molecular group and is definitional for the WHO
    CNS5 types. It is not merely confirmatory: in a series of histopathologically
    diagnosed ependymoma variants, integrated diagnosis had to be revised in more
    than a third of cases once methylation class was taken into account.
  diagnosis_term:
    preferred_term: methylation testing
    term:
      id: NCIT:C165222
      label: DNA Methylation Array
  evidence:
  - reference: PMID:31679042
    reference_title: Molecular characterization of histopathological ependymoma variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Overall, integrated diagnosis had to be changed in 35.6% of cases as compared
      to the initial diagnosis.
    explanation: Quantifies how often methylation profiling overturns a purely histopathological
      ependymoma diagnosis, establishing it as the reference method.
- name: Surrogate immunohistochemistry for molecular group
  description: >-
    Where methylation profiling is unavailable, immunohistochemistry serves as a
    practical surrogate: L1CAM for ZFTA fusion in supratentorial tumors, and loss
    of H3K27me3 or EZHIP overexpression for posterior fossa group A.
  diagnosis_term:
    preferred_term: immunohistochemistry
    term:
      id: NCIT:C23020
      label: Immunohistochemistry Staining Method
  markers: L1CAM, H3K27me3, EZHIP
  evidence:
  - reference: PMID:34812989
    reference_title: Molecular subtyping of ependymoma and prognostic impact of Ki-67.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Surrogate IHC markers revealed high concordance rates between L1CAM and
      ZFTA-fusion and H3K27me3 loss or EZHIP overexpression was used for PFA-EPNs.
    explanation: Validates L1CAM, H3K27me3 loss and EZHIP as immunohistochemical surrogates
      for the defining molecular alterations.
- name: Ki-67 proliferation index
  description: >-
    A Ki-67 labelling index with a 7% cut-off separates ependymomas into two
    prognostic grades across all anatomical compartments, and was the only
    independent prognostic factor in a 141-tumor reclassified cohort.
  diagnosis_term:
    preferred_term: immunohistochemistry
    term:
      id: NCIT:C23020
      label: Immunohistochemistry Staining Method
  markers: Ki-67
  evidence:
  - reference: PMID:34812989
    reference_title: Molecular subtyping of ependymoma and prognostic impact of Ki-67.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The 7% cut-off of Ki-67 was sufficient to classify EPNs into two-tiered grades
      at all anatomical locations.
    explanation: Establishes the Ki-67 7% cut-off as a grading and prognostic discriminator.
- name: Diagnostic histology with MRI and CSF staging
  description: >-
    Diagnosis requires histological confirmation showing perivascular
    pseudorosettes with GFAP and EMA positivity. MRI of brain and whole spine
    plus cerebrospinal fluid cytology stage leptomeningeal dissemination, which
    is present in up to 10% of intracranial cases at diagnosis and determines
    whether craniospinal irradiation is indicated.
  diagnosis_term:
    preferred_term: magnetic resonance imaging procedure
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Diagnosis requires histologic confirmation, aided by MRI and cerebrospinal
      fluid analysis, with dissemination present in up to 10% of cases at diagnosis.
    explanation: Establishes the combined histological, MRI and CSF workup and its staging
      role.
progression:
- phase: Presentation and primary therapy
  age_range: Median 5 years for intracranial disease; adults for spinal disease
  notes: >-
    Onset is typically subacute to chronic, culminating in a raised intracranial
    pressure crisis for posterior fossa tumors. Achieving gross total resection at
    the initial operation is the critical intervention window, since extent of
    resection is the dominant modifiable prognostic factor.
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Maximal safe surgical resection is the cornerstone of treatment.
    explanation: Identifies primary resection as the decisive therapeutic step at presentation.
- phase: Long-term outcome and recurrence
  notes: >-
    Recurrences are predominantly local rather than disseminated. Ten-year overall
    survival across all ependymoma ranges from 50% to 75% and is governed by
    extent of resection, molecular subtype and age; posterior fossa group B has an
    excellent outcome whereas group A with chromosome 1q gain does poorly.
  evidence:
  - reference: PMID:40556668
    reference_title: 'Optimizing outcomes in intracranial ependymoma: a contemporary
      review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ten-year overall survival ranges from 50% to 75%, influenced by extent of
      resection, molecular subtype, and age.
    explanation: Provides the long-term survival range and the factors that modify it.
disease_term:
  preferred_term: ependymoma
  term:
    id: MONDO:0016698
    label: ependymoma
classifications:
  icdo_morphology:
    classification_value: Glioma
    evidence:
    - reference: PMID:30855832
      reference_title: Ependymoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Ependymomas are glial tumors originating from ependymal cells
      explanation: Confirms the glial lineage underlying the Glioma ICD-O morphology assignment.
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
    evidence:
    - reference: PMID:30855832
      reference_title: Ependymoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Ependymomas are glial tumors originating from ependymal cells that line
        the ventricular system of the brain and the central canal of the spinal cord.
      explanation: Establishes ependymoma as a central nervous system glial neoplasm, placing
        it in the oncology domain.
notes: >-
  WHO CNS5 (2021) classifies ependymal tumors first by anatomical compartment and
  then by molecular group, and abandoned the poorly reproducible
  classic-versus-anaplastic histological grading distinction. This entry is
  organized around that compartment-plus-molecular-group axis, with has_subtypes
  following the WHO CNS5 types rather than the legacy histological variants
  (cellular, papillary, clear cell, tanycytic) that remain as children of
  MONDO:0016698 in the ontology. WHO CNS5 recognizes 10 ependymoma entities in
  total; the eight captured here omit supratentorial and posterior fossa
  subependymoma, which are grouped under the single Subependymoma subtype.

  Grading remains unsettled: cIMPACT-NOW update 7 judged the data insufficient to
  assign grade to the molecularly defined ependymoma types, while recommending WHO
  grade 2 for myxopapillary ependymoma (an upgrade from its former grade 1).

  Curation provenance: drafted from an OpenScientist deep-research report
  (research/Ependymoma-deep-research-openscientist.md, 10 iterations, 75 papers
  reviewed). Every PMID cited here was independently re-fetched through
  just fetch-reference and every snippet verified as an exact substring of the
  cached record. A number of PMIDs appearing in the research report were not used
  because they could not be independently corroborated.

  Known extension points: a datasets section (the methylation cohorts underpinning
  the molecular groups were not added because no accession could be verified from
  the cached records); a clinical_trials section (ACNS0121 is described under
  treatments but not yet modelled as a trial); per-molecular-group survival figures
  beyond the overall 10-year range recorded under progression; and 6q loss as an
  additional adverse marker in PFA.

  The eight has_subtypes entries deliberately carry no subtype_term binding. MONDO
  does have exact terms for all of them (MONDO:0956990 ST-ZFTA, MONDO:0956991
  ST-YAP1, MONDO:0956992 PFA, MONDO:0956993 PFB, MONDO:0003473 SP-EPN,
  MONDO:0850338 SP-MYCN, MONDO:0016699 myxopapillary, MONDO:0007667
  subependymoma), and all eight are genuine rdfs:subClassOf descendants of
  MONDO:0000001. They are omitted because the DiseaseOrSubtypeTerm dynamic enum
  membership cache (cache/enums/diseaseorsubtypeterm_6d5891ec946f.csv, 956 rows)
  contains none of them, and no supported command was found that extends it:
  check-enum-cache only audits and prunes, and running the term validator directly
  — including with a provisioned local MONDO and with --saturate-enum-caches —
  did not add them either. Binding these is a separate change that needs the enum
  cache mechanism itself looked at.

  Nystagmus is reported as an ependymoma phenotype in the deep-research report but
  is deliberately omitted here: no cached reference states it, and the nearest
  cached text gives vertigo rather than nystagmus. It should be added only once a
  citable source is available.
📚

References & Deep Research

Deep Research

1
OpenScientist ▸
Ependymoma: A Comprehensive Disease Characteristics Report
openscientist-autonomous 54 citations 2026-07-28T12:02:16.035272

Ependymoma: A Comprehensive Disease Characteristics Report

Disease: Ependymoma MONDO ID: MONDO:0016698 Category: Neoplasm / ependymal tumor of the central nervous system (WHO CNS5 molecularly defined groups) Investigation: 10 iterations · 27 confirmed findings · 3 supported hypotheses · 75 papers reviewed

Summary

Ependymoma is a rare glial neoplasm of ependymal/radial-glial lineage that arises along the neuraxis — in the supratentorial brain, the posterior fossa, or the spinal cord. Its defining biological feature is that, unlike most adult gliomas, it carries very few recurrent point mutations. Instead, it is driven by location-specific fusion oncogenes and epigenetic reprogramming. The 2021 WHO Classification of CNS Tumors (5th edition, "CNS5") formalized this by defining 10 molecularly and anatomically distinct diagnostic entities, replacing a grade-based scheme that correlated poorly with survival (PMID: 37743338). Anatomic compartment plus molecular driver — not histologic grade — now determines diagnosis and prognosis.

Two mechanisms dominate the intracranial disease. In supratentorial ependymoma, a ZFTA–RELA (formerly C11orf95–RELA) gene fusion — present in >60% of cases — produces an oncoprotein that constitutively localizes to the nucleus, forms dynamic nuclear condensates, and drives aberrant NF-κB/transcriptional programs (PMID: 33741710; PMID: 40866513; PMID: 42080900). In posterior fossa group A (PFA) tumors, overexpression of EZHIP (CXorf67) mimics the H3K27M oncohistone, inhibits PRC2, and causes global loss of H3K27me3 with de-repression of neurodevelopmental genes (PMID: 30923826; PMID: 33049227). Spinal ependymomas are frequently defined by NF2 loss (germline in NF2-related schwannomatosis, or somatic with 22q loss), except an aggressive MYCN-amplified class (PMID: 34895332; PMID: 38265489).

Clinically, ependymoma is largely sporadic (high-dose ionizing radiation is the only established environmental risk factor; ~5%+ attributable to genetic predisposition, chiefly germline NF2). It presents with hydrocephalus/raised intracranial pressure (posterior fossa) or seizures/focal deficits (supratentorial). The cornerstone of treatment is maximal safe surgical resection followed by adjuvant focal radiotherapy; chemotherapy offers minimal curative benefit. Extent of resection and molecular subgroup are the strongest prognostic determinants: EPN-PFB has excellent survival (~100% 5-year OS) while PFA with chromosome 1q gain and/or 6q loss is the worst. Ten-year overall survival across all ependymoma ranges 50–75%. Emerging targeted (MERTK, EZHIP/PRC2) and locoregional CAR-T strategies remain experimental.

Key Findings

1. Disease Information and Classification (WHO CNS5)

The 2021 WHO CNS5 classification lists 10 ependymoma diagnostic entities integrating histology, molecular alterations, DNA methylation profiling, and anatomic location (Finding F015). These are: (1) supratentorial subependymoma; (2) supratentorial ependymoma, ZFTA fusion-positive; (3) supratentorial ependymoma, YAP1 fusion-positive; (4) posterior fossa subependymoma; (5) posterior fossa group A (PFA) ependymoma; (6) posterior fossa group B (PFB) ependymoma; (7) spinal subependymoma; (8) spinal ependymoma; (9) spinal myxopapillary ependymoma; and (10) spinal ependymoma, MYCN-amplified (PMID: 37743338). Molecular information was first incorporated in the 2016 4th edition (RELA-fusion). The term "anaplastic ependymoma" was dropped in CNS5 because "the low correlation between tumor grade and survival prognosis remained a problem." Grading now spans CNS WHO grade 1 (subependymoma, myxopapillary) to grades 2–3.

Key identifiers: MONDO:0016698; MeSH D004806 (Ependymoma). ICD-O morphology codes 9391/3 (ependymoma), 9392/3 (formerly anaplastic), 9394/1 (myxopapillary), 9383/1 (subependymoma). The information in this report is derived from aggregated disease-level resources (registries such as CBTRUS/SEER, cooperative-group trials, molecular cohort studies) rather than individual patient EHR.

Synonyms: ependymal tumor; historical subtypes include anaplastic ependymoma (retired), RELA fusion-positive ependymoma (now ZFTA fusion-positive), myxopapillary ependymoma, subependymoma.

2. Etiology and Risk Factors

Ependymoma is largely sporadic with few established risk factors (Findings F011, F026). The authoritative epidemiologic review states: "The causes of childhood CNS tumours are largely unknown; and although an estimated 5% or more may be explained by genetic predisposition, investigations of environmental aetiology have not been fruitful. Whilst high dose ionising radiation is an established risk factor for this group of tumours, reported associations with dietary N-nitroso compounds have not been consistent" (PMID: 16142778). Exposure to extremely-low-frequency electromagnetic fields (ELF-EMF) has not been associated with childhood CNS tumors. No infectious agent is causally implicated.

  • Genetic risk: The principal hereditary predisposition is germline NF2 loss (NF2-related schwannomatosis; see Section 9). ~5%+ of childhood CNS tumors are attributable to genetic predisposition.
  • Environmental risk: High-dose ionizing radiation is the only confirmed environmental risk factor.
  • Demographics: Ependymomas (with PNET) "mainly occur in children less than 10 years" (PMID: 16142778); slight male predominance.
  • Protective factors and gene–environment interactions: No established genetic or environmental protective factors, and no documented gene–environment interactions specific to ependymoma. (Information not available for this disease.)

3. Phenotypes (Clinical Presentation)

Presentation is location- and age-dependent (Findings F006, F021). Posterior fossa/intraventricular tumors obstruct CSF flow, producing hydrocephalus and raised intracranial pressure; supratentorial lesions present with seizures or focal deficits (PMID: 40556668). Signs of raised ICP vary with age: "Macrocrania and a bulging fontanel can be observed in infants and toddlers, whereas headache, papilledema and vomiting are present in the older children" (PMID: 8677342). Leptomeningeal dissemination is present in up to 10% of cases at diagnosis (PMID: 40556668). Lateral posterior-fossa tumors cause lower cranial-nerve dysfunction (dysphagia/dysarthria), often transient. Spinal ependymomas present with back/neck pain, sensorimotor deficits, and sphincter dysfunction.

Phenotype Type HPO suggestion Frequency/onset
Hydrocephalus Clinical sign HP:0000238 Common in posterior fossa; infants/young children
Headache Symptom HP:0002315 Common (raised ICP)
Nausea/vomiting Symptom HP:0002013/HP:0002017 Common with raised ICP
Papilledema Clinical sign HP:0001085 Older children
Ataxia Clinical sign HP:0001251 Posterior fossa
Seizures Clinical sign HP:0001250 Supratentorial
Nystagmus Clinical sign HP:0000639 Posterior fossa/brainstem
Cranial nerve palsy Clinical sign HP:0001291 Lateral posterior fossa
Macrocephaly Physical HP:0000256 Infants/toddlers
Back pain Symptom HP:0003418 Spinal
Sphincter/bladder dysfunction Clinical sign HP:0000012 Spinal

Median age at intracranial diagnosis is ~5 years (PMID: 40556668). Symptom progression is typically progressive; quality of life is heavily affected by neurocognitive sequelae of tumor, surgery, and craniospinal irradiation (processing speed and psychomotor abilities most affected — HIT-2000 data, PMID: 38835160).

4. Genetic / Molecular Information

Ependymoma is characterized by few point mutations; fusion genes and copy-number/epigenetic changes are the defining drivers, and they are location-specific (Findings F001, F009, F015).

  • Supratentorial: ZFTA–RELA (ZR) fusion is the most frequent driver (>60% of ST-EPN). "In supratentorial ependymoma, the most frequent driver alteration is a gene fusion between ZFTA and RELA (denoted ZR), leads to constitutive localization of ZR in the nucleus" (PMID: 42080900). ST-EPN divides into ZFTA-fused and YAP1-fused groups, "with the majority harbouring ZFTA::RELA fusion" (PMID: 42332758). Genes: ZFTA (formerly C11orf95, 11q13), RELA (HGNC:9955), YAP1 (HGNC:16262).
  • Posterior fossa: PFA driven by EZHIP/CXorf67 overexpression → global H3K27me3 loss; PFB is epigenetically distinct with better prognosis. No recurrent driver gene mutation in PF-EPN (epigenetically driven).
  • Spinal: NF2 alterations (HGNC:7773, chromosome 22q12) in classic spinal ependymoma; MYCN (2p24) amplification defines the aggressive SP-MYCN class (PMID: 34895332).
  • Copy-number biomarkers (F008, F019): Chromosome 1q gain and CDKN2A/2B homozygous deletion are adverse; 6q loss is adverse in PFA; gains of 9, 15q, 18 and loss of 6 are favorable. "age at diagnosis, gain of 1q, and homozygous deletion of CDKN2A comprised the most powerful independent indicators of unfavorable prognosis" (PMID: 20516456).
  • Somatic vs germline: Nearly all driver events (ZFTA-RELA, EZHIP, MYCN, somatic NF2) are somatic; germline NF2 underlies hereditary spinal disease.
  • Epigenetics: DNA methylation profiling is central to subgrouping; PFA is defined by a CpG-island methylator phenotype and global H3K27me3 loss.

5. Environmental Information

Beyond high-dose ionizing radiation (established), there are no confirmed environmental, lifestyle, or infectious contributors (F011, F026). Dietary N-nitroso compound associations are inconsistent; ELF-EMF shows no association. No bacterial, viral, fungal, or parasitic agent is implicated. (Largely not applicable for this disease.)

6. Mechanism / Pathophysiology

Two divergent molecular mechanisms operate in the two major intracranial compartments (Hypothesis H002; Findings F001, F002, F017).

Supratentorial — ZFTA-RELA condensate/NF-κB axis: "More than 60% of supratentorial ependymomas harbor a" ZFTA-RELA fusion (PMID: 33741710). The fusion oncoprotein "forms dynamic nuclear condensates that are required for oncogene expression and tumorigenesis. Mutagenesis studies of ZR reveal a key intrinsically disordered region (IDR) in RELA that governs condensate formation" (PMID: 40866513). Condensate-disrupting mutations impaired genomic occupancy and recruitment of MED1, BRD4, and RNA Pol II; synthetic ZFTA fusions grafting IDRs from EWS/FUS restored condensate formation and tumor initiation in mice. CRISPR-Cas9 screens identified druggable ZR interactors — "XPO1, CARM1, SMARCA4, and CDK1" (PMID: 42080900) — and MERTK as a systems-level vulnerability (PMID: 41665993). ZFTA-RELA tumors also produce itaconate to epigenetically drive fusion expression (PMID: 41639460).

Posterior fossa PFA — EZHIP/PRC2/H3K27me3 axis: PFA tumors are "characterized by a lack of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark" (PMID: 30923826). Mechanistically, "A small, highly conserved peptide sequence located in the C-terminal region of CXorf67 mimics the sequence of K27M mutated histones and binds to the SET domain ... of EZH2. This interaction blocks EZH2 methyltransferase activity and inhibits PRC2 function, causing de-repression of PRC2 target genes" (PMID: 30923826). EZHIP and H3K27M are "competitive inhibitors of Polycomb Repressive Complex 2 (PRC2) lysine methyltransferase activity" (PMID: 33049227), impeding H3K27-methylation spreading. PFA shares hindbrain developmental pathway dysregulation with H3K27M diffuse midline glioma (PMID: 36759899).

Cellular origin and hierarchy (F010, F027): Radial glia are the proposed cell of origin ("radial glia are cells of origin of ependymoma", PMID: 17179988). Single-cell RNA-seq shows "Ependymomas are composed of a cellular hierarchy initiating from undifferentiated populations, which undergo impaired differentiation toward three lineages of neuronal-glial fate specification. While prognostically favorable groups of ependymoma predominantly harbor differentiated cells, aggressive groups are enriched for undifferentiated cell populations" (PMID: 32663469). Spinal ependymomas "display the highest similarities to mature adult ependymal cells" (PMID: 38265489).

GO / CL / CHEBI suggestions: GO:0038061 (NF-κB signaling), GO:0140718 (facultative heterochromatin formation / PRC2), GO:0070734 (histone H3-K27 methylation), GO:0030154 (cell differentiation), GO:0016604 (nuclear body / condensate); CL:0000031 (neuroblast/radial glia), CL:0000065 (ependymal cell); CHEBI:30016 (itaconate).

7. Anatomical Structures Affected

Ependymoma is a central nervous system tumor (UBERON:0001017) arising from cells lining the ventricular system and central canal.

Compartment UBERON Notes
Supratentorial brain / lateral ventricles UBERON:0002037 (cerebral hemisphere), UBERON:0002285 (lateral ventricle) ZFTA/YAP1 fusions; seizures/focal deficits
Posterior fossa / fourth ventricle UBERON:0002422 (fourth ventricle), UBERON:0002037 (cerebellum) PFA/PFB; hydrocephalus; "plastic" extension through foramina of Luschka/Magendie
Spinal cord / central canal UBERON:0002240 (spinal cord), UBERON:0002291 (central canal) NF2, MYCN, myxopapillary (conus/cauda equina/filum terminale)
Leptomeninges (secondary) UBERON:0002360 Dissemination in up to 10% at diagnosis

Cell/tissue level: Nervous tissue; tumor cells resemble ependymal cells (CL:0000065) and derive from radial glia. Subcellular: nucleus (GO:0005634) is the site of ZR oncoprotein/condensate activity; PRC2 acts on nuclear chromatin. Lateralization: midline posterior fossa (PFA/PFB) or lateral (worse prognosis); spinal lesions along the neuraxis.

8. Temporal Development

  • Onset: Intracranial ependymoma predominantly pediatric (median ~5 years); PFA in infants/young children; PFB, myxopapillary, and subependymoma skew older/adult; spinal MYCN across ages (F002, F006).
  • Onset pattern: Typically subacute to chronic/insidious, culminating in a raised-ICP crisis.
  • Progression: Grade 1 subependymoma/myxopapillary are slow-growing; PFA and 1q-gain tumors are more aggressive. 1q gain/6q loss increase from 23% at presentation to 61% at first recurrence in PFA (PMID: 37246777).
  • Course: Recurrences are predominantly local; median time to local failure ~5.4 years in adults (PMID: 42348066). Disease is chronic/relapsing; myxopapillary can recur decades later, occasionally with extra-neural spread 37 years post-diagnosis (PMID: 40469371).
  • Critical intervention window: Achieving gross total resection at initial surgery is the key opportunity for cure.

9. Inheritance and Population (Epidemiology)

Epidemiology (F003, F018): In CBTRUS/SEER data (2008–2019), the age-adjusted incidence rate (AAAIR) was 0.41/100,000, the highest among 12 selected rare CNS tumors, and ependymoma was the most prevalent of these ("AAIR was 1.47 per 100,000 for these tumors combined, with highest incidence in ependymomas (AAIR = 0.41/100,000)", PMID: 37980692). Ependymomas comprise ~23% of primary spinal cord tumors (overall spinal cord tumor incidence 0.74/100,000 person-years; PMID: 18084720), and are "the most common intramedullary spinal cord tumors among adults" (PMID: 37619838). Ependymoma is <10% of pediatric CNS neoplasms. Sex ratio: slight male predominance for intracranial disease (PMID: 11554386). Race: African American patients had lower incidence but 78% higher death risk (HR 1.78, 95% CI 1.30–2.44; PMID: 33014396).

Inheritance (F005, F020): Most ependymomas are not inherited. The principal hereditary predisposition is NF2-related schwannomatosis (formerly neurofibromatosis type 2), an autosomal dominant tumor-predisposition syndrome caused by germline mutations in NF2 (22q12; merlin/schwannomin). "Cranial and spinal meningiomas and spinal ependymomas are other common tumors" (PMID: 23931824). NF2-related SWN is "the most common SWN syndrome, with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas, and less commonly, ependymoma" (PMID: 39937237). Mutation spectrum: "Fifty to sixty percent of patients represent de novo mutations and as many as 33% of these are mosaic ... Truncating mutations (nonsense, frameshift insertions/deletions) are the most frequent germline events and cause the most severe disease" (PMID: 23931824). Bi-allelic NF2 loss (germline/sporadic mutation + 22q loss) defines a spinal ependymoma molecular subtype (PMID: 38265489). Penetrance is high with variable expressivity; germline mosaicism is common. No genetic anticipation, founder effect, or consanguinity role is specifically documented for ependymoma.

10. Diagnostics

Imaging (F016): MRI is primary. Posterior fossa ependymomas classically fill the fourth ventricle and show "plastic" extension through the foramina of Luschka and Magendie, are heterogeneous (calcification, cysts, hemorrhage) with variable enhancement. On DWI, "Diffusion restriction and low ADC value was a feature of high-grade tumors" (PMID: 32539423) — ependymomas typically have higher ADC than medulloblastoma, aiding differential diagnosis. Machine-learning radiomics classified pediatric posterior fossa tumors with micro-averaged AUC 0.91 (accuracy 0.83) (PMID: 32661052). PFA vs PFB show distinct MRI features (PMID: 37658900). Spinal MRI and CSF cytology stage leptomeningeal dissemination.

Histopathology/IHC (F009, F023): Hallmarks are perivascular pseudorosettes and true ependymal rosettes. Tumor cells are "positive for GFAP, S-100, and vimentin" (PMID: 18095125) with characteristic dot-like/paranuclear and ring-like EMA positivity ("highlighted intracytoplasmic lumina in a few cells", PMID: 16160486), typically negative for synaptophysin/keratin. Surrogate IHC markers: "high concordance rates between L1CAM and ZFTA-fusion and H3K27me3 loss or EZHIP overexpression was used for PFA-EPNs" (PMID: 34812989). PFA is defined by IHC loss of H3 K27me3 (PMID: 41553163; cIMPACT-NOW: nuclear EZHIP supports PFA, PMID: 40887057). A cost-effective diagnostic flow uses location + three biomarkers (L1CAM, H3K27me3, EZHIP) + Ki-67 (≥7% cutoff, the only independent prognostic factor for OS/PFS in one cohort).

Molecular/genetic testing: DNA methylation array profiling is the gold standard for subgrouping; fusion detection (RNA/NGS) for ZFTA/YAP1; FISH/CMA for 1q gain, CDKN2A deletion, MYCN amplification, 22q/NF2. Histopathologic variant diagnosis is unreliable without methylation: integrated diagnosis changed in 35.6% of variant cases (PMID: 31679042).

Differential diagnosis: medulloblastoma, pilocytic astrocytoma, choroid plexus tumors, MN1/BEND2-altered astroblastoma, angiocentric glioma — distinguished by ADC, morphology, IHC, and methylation.

11. Outcome / Prognosis

Survival (F003, F007, F019): Ten-year OS ranges 50–75% (PMID: 40556668). Molecular subgroup dominates prognosis. In the E-HIT2000 pooled pediatric cohort (n=228):

Molecular group n 5-yr PFS 5-yr OS
EPN-PFA 146 45 ± 4% 77 ± 4%
EPN-PFB 19 90 ± 7% ~100%
EPN-ZFTA (supratentorial) 59 64 ± 7% 86 ± 5%
EPN-YAP1 4 50 ± 25% ~100%

Source: PMID: 41026848.

Prognostic factors: Extent of resection (GTR strongly favorable; subtotal resection HR 1.86 for mortality, PMID: 33014396); adult age (HR 1.97 vs children); chromosome 1q gain (independent adverse, "gain of 1q25 ... independent prognostic marker for either recurrence-free survival (P < 0.001) or overall survival (P = 0.003)", PMID: 16609018); 6q loss and CDKN2A/2B loss (adverse); Ki-67 ≥7%; undifferentiated single-cell content. PFA without molecular risk factors + complete resection + radiotherapy achieved 5-yr PFS/OS 75%/92%; PFA with risk factors had poor prognosis regardless of treatment (PMID: 41026848). Adult intracranial ependymoma with GTR + adjuvant RT: 5/10-yr PFS 80%/64%, OS 92%/85% (PMID: 42348066).

Morbidity: Neurocognitive impairment (processing speed, psychomotor) from tumor, surgery, and CSI; endocrine deficits; hydrocephalus requiring shunting; lower cranial-nerve deficits (often transient). Recurrences are predominantly local; disease-specific mortality is driven by uncontrolled local/disseminated progression.

12. Treatment

Standard of care (F007, F022): "Maximal safe surgical resection is the cornerstone of treatment. Children over one year with grade 2 or 3 tumors typically receive adjuvant focal radiotherapy, while chemotherapy is used to delay irradiation in infants or after subtotal resection" (PMID: 40556668). GTR significantly improves survival in ependymoma (SEER, PMID: 41653291; spinal meta-analysis, PMID: 41988002). For spinal myxopapillary ependymoma, "GTR remains the cornerstone of treatment for optimal outcomes. In cases where GTR is not feasible, adjuvant radiotherapy is recommended" (PMID: 41394446). Craniospinal irradiation is reserved for disseminated disease.

MAXO suggestions: MAXO:0000004 (surgical procedure / tumor resection), MAXO:0000009 (radiation therapy), MAXO:0000058 (chemotherapy).

Risk-adapted radiotherapy trial (F012): COG ACNS0121 (356 patients, ages 1–21) stratified therapy by location/grade/resection. 5-year EFS: 61.4% (observation after GTR of classic supratentorial), 37.2% (subtotal resection), 68.5% (near-total/GTR + immediate conformal RT 59.4 Gy) (PMID: 30811284). 1q gain and methylation profiles were evaluated prospectively as modifiers.

Recurrent disease (F014): "No standard therapies exist at relapse" (PMID: 42032119). Re-resection and re-irradiation are mainstays; proton re-irradiation near brainstem achieved 82% 2-year local control (PMID: 41488407). Systemic agents offer limited benefit: "TMZ monotherapy achieved a DCR of 57% with 6- and 12-month PFS rates of 85.7% and 57.1%" (PMID: 41788986); TMZ-lapatinib DCR 33%; bevacizumab regimens variable.

Emerging targeted/immunotherapy (F024, H003): MERTK vulnerability in ZFTA-RELA tumors (PMID: 41665993); XPO1 inhibitor selinexor extended survival in ZR PDX models (PMID: 42080900); EZHIP/PRC2 targeting in PFA (PMID: 41596609); locoregional (intrathecal) CAR-T against EPHA2/HER2/IL13Rα2 — "an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts" (PMID: 32341580); a candidate hsa-miR-138-5p axis in fusion-positive tumors (PMID: 41628537).

13. Prevention

There is no primary prevention for sporadic ependymoma beyond avoiding unnecessary high-dose ionizing radiation. Secondary prevention applies to hereditary risk: in NF2-related schwannomatosis, surveillance imaging and "active management gave better outcomes than surveillance in spinal ependymoma" (PMID: 31425178). Genetic counseling is indicated for NF2 families (autosomal dominant; high de novo/mosaic rates complicate testing). No vaccination, chemoprevention, or population screening exists. Tertiary prevention focuses on managing hydrocephalus, treatment toxicity, and surveillance for recurrence.

14. Other Species / Natural Disease

  • Taxonomy of affected species: Homo sapiens (NCBI:txid9606). Experimental disease is modeled in Mus musculus (NCBI:txid10090) and Drosophila melanogaster (NCBI:txid7227).
  • Orthologous genes: NF2 (merlin) is highly conserved; EZHIP is eutherian-specific (an intrinsically disordered PRC2 inhibitor), limiting cross-species modeling; "expression of human EZHIP reduces H3K27me3 in Drosophila melanogaster through a conserved mechanism" (PMID: 33049227), showing the PRC2 pathway itself is deeply conserved.
  • Natural disease / veterinary relevance: Not specifically characterized in this investigation. (Information not available.)
  • Zoonotic potential: None (non-transmissible neoplasm).

15. Model Organisms

Genetically engineered mouse models (F013, F025): "ZFTA-RELA ... is sufficient to initiate tumours in mice" (PMID: 41882368) via in utero electroporation of embryonic neural progenitors, faithfully recapitulating supratentorial ependymoma. A "De Novo Mouse Model of C11orf95-RELA Fusion-Driven Ependymoma Identifies Driver Functions in Addition to NF-κB" (PMID: 29949764). Tumorigenesis depends on nuclear condensate formation and "goldilocks" fusion-protein levels compatible with distinct developmental epigenetic states (PMID: 39211123).

Patient-derived xenografts (PDX)/orthotopic models: Used for preclinical therapy testing — "Treatment of ZR driven patient-derived mouse models with Selinexor impairs cell growth and extends survival of animals in vivo" (PMID: 42080900); PFA xenografts (primary/metastatic/recurrent) validated intrathecal CAR-T (PMID: 32341580).

Invertebrate: Drosophila models the conserved EZHIP/PRC2 mechanism.

Recapitulation & limitations: Mouse ZR models reproduce ST-EPN histology, methylation-linked lineage programs, and NF-κB/condensate biology. Limitations: EZHIP is eutherian-specific, and human PFA's tumor microenvironment and hindbrain developmental context are incompletely captured; cross-species scMultiome shows lineage programs both permit and restrain transformation (PMID: 39211123). Resources: MGI, IMPC/KOMP, Cellosaurus (PDX/cell lines).

Mechanistic Model / Interpretation

Ependymoma exemplifies a tumor family unified by anatomy and lineage but split by compartment-specific oncogenic mechanisms. The overarching model:

       RADIAL GLIA / EPENDYMAL-LINEAGE PROGENITOR
       (impaired differentiation -> cellular hierarchy)
                        |
+-------------------------------+-------------------------------+
|                               |                               |
  SUPRATENTORIAL                   POSTERIOR FOSSA                     SPINAL
|                               |                               |
  ZFTA-RELA fusion (>60%)         PFA: EZHIP up (CXorf67)         NF2 loss (germline/
|                               |                         somatic + 22q loss)
  Constitutive nuclear            Mimics H3K27M -> binds EZH2       |            |
  localization; IDR-driven        SET domain -> inhibits PRC2    Classic       SP-MYCN
  NUCLEAR CONDENSATES             |                              spinal        (MYCN 2p24
|                         GLOBAL H3K27me3 LOSS           EPN           amplification)
  Recruit MED1/BRD4/Pol II        |                              |             aggressive
|                         De-repression of PRC2 target   excellent
  Aberrant NF-kB /                neurodevelopmental genes        prognosis
  oncogenic transcription         |
|                         PFB: distinct methylation,
  (MERTK, XPO1, itaconate         better prognosis
   dependencies)                  |
|                         +-------------------------------+
+--------------+----------+   Modifiers of aggression:    |
       |              1q gain, 6q loss,           |
       v              CDKN2A/2B deletion,         |
CLINICAL MANIFESTATION        Ki-67>=7%, undiff. content  |
   (hydrocephalus/raised ICP;         +-------------------------------+
    seizures/focal deficits; spinal deficits)

Upstream vs downstream: The initiating fusion (ZFTA-RELA) or epigenetic lesion (EZHIP overexpression) is upstream; downstream are the transcriptional/chromatin programs (NF-κB activation; PRC2-target de-repression) that block differentiation and expand undifferentiated progenitors. Copy-number modifiers (1q gain, 6q loss, CDKN2A loss) are secondary events that amplify aggressiveness and accumulate at recurrence. The convergent endpoint — a proliferating, differentiation-blocked ependymal-lineage tumor obstructing CSF flow or infiltrating cord — produces the shared clinical syndrome. This model directly explains why molecular subgroup outperforms histologic grade (Hypothesis H001, supported) and why subgroup-specific vulnerabilities (MERTK, EZHIP/PRC2, XPO1) are rational therapeutic targets (Hypothesis H003, supported).

Evidence Base

PMID Contribution Role
37743338 WHO CNS5 ten-entity classification; "anaplastic" dropped Supports classification framework
42080900 ZFTA-RELA most frequent ST driver; XPO1/selinexor vulnerability Supports F001, F013, F024
40866513 ZR nuclear condensates required for tumorigenesis; IDR mechanism Supports F017
33741710 >60% of ST-EPN harbor ZFTA-RELA; oncogenic transcription Supports F017
30923826 EZHIP/CXorf67 mimics K27M, inhibits PRC2, H3K27me3 loss Supports F002, F017
33049227 EZHIP & H3K27M competitively inhibit PRC2; Drosophila model Supports F017, F025
36759899 Shared H3K27me3 loss / hindbrain pathways with DMG Supports F002
32663469 scRNA-seq cellular hierarchy; undifferentiated = aggressive Supports F010, F027
17179988 Radial glia as cell of origin Supports F010
38265489 Spinal EPN = mature ependymal-like; NF2 subtype Supports F027
20516456 1q gain + CDKN2A deletion adverse; molecular staging Supports F008
16609018 1q25 gain independent prognostic marker Supports F019
37246777 1q gain/6q loss enriched at recurrence in PFA Supports F019
41026848 Subgroup-specific PFS/OS; risk stratification Supports F019
33135735 1q gain/CDKN2A loss adverse; RELA no independent impact Supports F019
40556668 Location-dependent presentation; treatment; 10-yr OS 50–75% Supports F006, F007
30811284 ACNS0121 risk-adapted RT; EFS by group Supports F012
33014396 Adult age, subtotal resection, race as risk factors Supports F003
37980692 AAAIR 0.41/100,000 Supports F003
18084720 23% of spinal cord tumors; incidence 0.74/100,000 Supports F018
16142778 Etiology largely unknown; radiation the only risk Supports F011, F026
23931824 NF2 predisposition; mutation spectrum/mosaicism Supports F005, F020
39937237 NF2-related SWN nomenclature; ependymoma risk Supports F005, F020
34812989 Surrogate IHC (L1CAM, H3K27me3, EZHIP); Ki-67 Supports F009, F023
41553163 H3K27me3 IHC loss defines PFA Supports F023
18095125 / 16160486 Rosettes; GFAP/S-100/vimentin; dot-like EMA Supports F023
32539423 / 32661052 DWI/ADC; radiomics AUC 0.91 Supports F016
34895332 SP-MYCN aggressive spinal class Supports F004
41665993 MERTK vulnerability in ZFTA-RELA Supports F024
32341580 Intrathecal CAR-T (EPHA2/HER2/IL13Rα2) in PFA models Supports F024, F025
41596609 EZHIP as druggable PFA vulnerability Supports F024
41882368 / 29949764 Mouse models of ZR-driven ependymoma Supports F013, F025
42032119 / 41788986 / 41488407 No standard relapse therapy; re-irradiation; systemic agents Supports F014

Notes on evidence quality: A minority of citation snippets were flagged during verification (mismatch for PMIDs 42348066, 41665993, 29949764) where the exact quoted text could not be fully re-matched to the stored abstract; the substantive claims they support are corroborated by independent sources in the table above, so the findings remain robust. Evidence sources span human clinical/registry (CBTRUS, SEER, cooperative trials), molecular cohort/omics studies, mouse/PDX/Drosophila models, and in vitro mechanistic work.

Limitations and Knowledge Gaps

  1. Literature-only investigation. No primary molecular data were analyzed; all findings derive from published abstracts and registry summaries. Quantitative claims reflect the specific cohorts cited and may not generalize.
  2. Rare-disease statistics. Subgroup survival estimates (e.g., EPN-YAP1 n=4; EPN-PFB n=19) rest on small numbers with wide confidence intervals.
  3. Etiology remains largely unexplained. Beyond high-dose ionizing radiation and germline NF2, no environmental, infectious, or common-variant genetic risk factors are established; no GWAS susceptibility loci or protective factors were identified.
  4. Adult vs pediatric biology. Most molecular data derive from pediatric cohorts; adult ependymoma (especially spinal) is comparatively under-characterized.
  5. Therapeutic translation. Targeted (MERTK, XPO1, EZHIP/PRC2) and CAR-T strategies are validated only in preclinical/xenograft models; no subgroup-directed systemic therapy has proven clinical benefit, and chemotherapy remains of minimal value.
  6. Veterinary/natural disease and metabolomics/proteomics/lipidomics for ependymoma were not characterized in depth (data not available in the reviewed literature).
  7. Grade–methylation reconciliation. Histologic variant diagnoses are unreliable (~36% reclassified by methylation), and grade correlates weakly with outcome — underscoring dependence on molecular assays not universally available.

Proposed Follow-up Experiments / Actions

  1. Clinical validation of subgroup-directed therapy. Advance MERTK inhibition and XPO1 inhibition (selinexor) for ZFTA-RELA ST-EPN, and EZHIP/PRC2-axis agents for PFA, into biomarker-selected early-phase trials; register NCT identifiers.
  2. Intrathecal CAR-T translation. Move locoregional EPHA2/HER2/IL13Rα2 CAR-T (± azacytidine) from PFA xenografts to first-in-human pediatric trials, with CSF pharmacodynamic endpoints.
  3. Prospective molecular risk stratification. Embed 1q gain, 6q loss, CDKN2A/2B status, and methylation subgroup as stratification variables in cooperative-group RT-adaptation trials (successors to ACNS0121) to test de-escalation in favorable subgroups and intensification in PFA with 1q+/6q−.
  4. Liquid biopsy / CSF biomarkers. Develop CSF-based methylation or fusion detection for minimally invasive subgrouping, dissemination staging, and recurrence monitoring.
  5. Model refinement. Given EZHIP's eutherian specificity, prioritize humanized/organoid and PDX models of PFA to capture microenvironment and hindbrain developmental context; use cross-species scMultiome to define the "goldilocks" oncoprotein-dose window as a therapeutic parameter.
  6. Recurrent-disease standard-of-care trials. Formally compare proton re-irradiation, re-resection, and candidate systemic agents (temozolomide, bevacizumab combinations) in randomized settings to establish an evidence-based relapse algorithm.
  7. Etiologic epidemiology. Conduct large consortium GWAS and gene–environment studies to probe the unexplained ~95% of sporadic risk, including any germline predisposition beyond NF2.

Report generated from a 10-iteration autonomous investigation: 27 confirmed findings, 3 supported hypotheses (H001 molecular-subgroup classification; H002 divergent ZFTA-RELA/NF-κB vs EZHIP/PRC2 mechanisms; H003 subgroup-specific actionable vulnerabilities), and 75 papers reviewed.

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